Quinoline compounds suitable for treating disorders that respond to the modulation of the serotonin 5-ht6 receptor

ABSTRACT

The present invention relates to quinoline compounds of formula I 
     
       
         
         
             
             
         
       
     
     wherein the variables are defined as in the claims and the description. The invention further relates to a pharmaceutical composition containing such compounds, to their use as modulators of the 5-HT 6  receptor, their use for preparing a medicament for the prevention or treatment of conditions and disorders which respond to the modulation of the 5-HT 6  receptor, and to methods for preventing or treating conditions and disorders which respond to the modulation of the 5-HT 6  receptor.

FIELD OF THE INVENTION

The present invention relates to specific quinoline compounds, to apharmaceutical composition containing such compounds, to their use asmodulators of the 5-HT₆ receptor, their use for preparing a medicamentfor the prevention or treatment of conditions and disorders whichrespond to the modulation of 5-HT₆ receptor, to methods for preventingor treating conditions and disorders which respond to the modulation of5-HT₆ receptor, and processes for preparing such compounds andcompositions.

BACKGROUND OF THE INVENTION

Serotonin (5-hydroxytryptamine, 5-HT), a monoamine neurotransmitter andlocal hormone, is formed by the hydroxylation and decarboxylation oftryptophan. The greatest concentration is found in the enterochromaffincells of the gastrointestinal tract, the remainder being predominantlypresent in platelets and in the Central Nervous System (CNS). 5-HT isimplicated in a vast array of physiological and pathophysiologicalpathways. In the periphery, it contracts a number of smooth muscles andinduces endothelium-dependent vasodilation. In the CNS, it is believedto be involved in a wide range of functions, including the control ofappetite, mood, anxiety, hallucinations, sleep, vomiting and painperception.

Neurons that secrete 5-HT are termed serotonergic. The function of 5-HTis exerted upon its interaction with specific (serotonergic) neurons.Seven types of 5-HT receptors have been identified: 5-HT₁ (with subtypes5-HT_(1A), 5-HT_(1B), 5-HT_(1D), 5-HT_(1E) and 5-HT_(1F)), 5-HT₂ (withsubtypes 5-HT_(2A), 5-HT_(2B) and 5-HT₂c), 5-HT₃, 5-HT₄, 5-HT₅ (withsubtypes 5-HT_(5A) and 5-HT_(5B)), 5-HT₆ and 5-HT₇. Most of thesereceptors are coupled to G-proteins that affect the activities of eitheradenylate cyclase or phospholipase Cγ.

The human 5-HT₆ receptors are positively coupled to adenylyl cyclase.They are distributed throughout the limbic, striatal and corticalregions of the brain and show a high affinity to antipsychotics.

The modulation of the 5-HT₆ receptor by suitable substances is expectedto improve certain disorders including cognitive dysfunctions, such as adeficit in memory, cognition and learning, in particular associated withAlzheimer's disease, age-related cognitive decline and mild cognitiveimpairment, attention deficit disorder/hyperactivity syndrome,personality disorders, such as schizophrenia, in particular cognitivedeficits related with schizophrenia, affective disorders such asdepression, anxiety and obsessive compulsive disorders, motion or motordisorders such as Parkinson's disease and epilepsy, migraine, sleepdisorders (including disturbances of the Circadian rhythm), feedingdisorders, such as anorexia and bulimia, certain gastrointestinaldisorders such as Irritable Bowel Syndrome, diseases associated withneurodegeneration, such as stroke, spinal or head trauma and headinjuries, such as hydrocephalus, addiction diseases and obesity (seee.g. A. Meneses, Drug News Perspect 14(7) (2001) pp. 396-400 andliterature cited therein; J. Pharmacol. Sci. Vol. 101 (Suppl. 1), 2006,p. 124. Modulators of the 5HT₆-receptor such as PRX-07034 (EpixPharmaceuticals) have been found in preclinical and clinical studies tobe particular useful in the treatment of cognitive dysfunctions, inparticular associated with Alzheimer's disease or schizophrenia or inthe treatment of obesity (see e.g.http://www.epixpharma.com/products/prx-07034.asp).

Compounds with a structural similarity to the compounds of the presentinvention have been described in WO 03/080580, WO 2005/113539, WO2007/039219, WO 2007/039238 and WO 2009/019286.

However, there is still an ongoing need for providing compounds havinghigh affinity for the 5-HT₆ receptor and which advantageously also showhigh selectivity to this receptor.

Besides the binding affinity for the 5-HT₆ receptor, further propertiesmay be advantageous for the treatment and/or prophylaxis of5-HT₆-dependent disorders, such as, for example:

1.) a selectivity for the 5-HT₆ receptor compared with the 5-HT_(1A)receptor, i.e. the quotient of the binding affinity for the 5-HT_(1A)receptor (Ki(5-HT_(1A)) (determined in the unit “nanomolar (nM)”) andthe binding affinity for the 5-HT₆ receptor (Ki(5-HT₆)) (determined inthe unit “nanomolar (nM)”). A larger quotient Ki(5-HT_(1A))/Ki(5-HT₆)means a greater 5-HT₆ selectivity;

2.) a selectivity for the 5-HT₆ receptor compared with the 5-HT_(2A)receptor, i.e. the quotient of the binding affinity for the 5-HT_(2A)receptor (Ki(5-HT_(2A)) (determined in the unit “nanomolar (nM)”) andthe binding affinity for the 5-HT₆ receptor (Ki(5-HT₆)) (determined inthe unit “nanomolar (nM)”). A larger quotient Ki(5-HT_(2A))/Ki(5-HT₆)means a greater 5-HT₆ selectivity.

3.) a selectivity for the 5-HT₆ receptor compared with the 5-HT_(2B)receptor, i.e. the quotient of the binding affinity for the 5-HT_(2B)receptor (Ki(5-HT_(2B)) (determined in the unit “nanomolar (nM)”) andthe binding affinity for the 5-HT₆ receptor (Ki(5-HT₆)) (determined inthe unit “nanomolar (nM)”). A larger quotient Ki(5-HT_(2B))/Ki(5-HT₆)means a greater 5-HT₆ selectivity.

4.) a low affinity to adrenergic receptors, such as α₁-adrenergicreceptor, histamine receptors, such as H₁-receptor, and dopaminergicreceptors, such as D₂-receptor, in order to avoid or reduce considerableside effects associated with modulation of these receptors, such aspostural hypotension, reflex tachycardia, potentiation of theantihypertensive effect of prazosin, terazosin, doxazosin and labetalolor dizziness associated to the blockade of the α₁-adrenergic receptor,weight gain, sedation, drowsiness or potentiation of central depressantdrugs associated to the blockade of the H₁-receptor, or extrapyramidalmovement disorder, such as dystonia, parkinsonism, akathisia, tardivedyskinesia or rabbit syndrome, or endocrine effects, such as prolactinelevation (galactorrhea, gynecomastia, menstruyl changes, sexualdysfunction in males), associated to the blockade of the D₂-receptor.

5.) the metabolic stability, for example determined from the half-lives,measured in vitro, in liver microsomes from various species (e.g. rat orhuman);

6.) no or only low inhibition of cytochrome P450 (CYP) enzymes:cytochrome P450 (CYP) is the name for a superfamily of heme proteinshaving enzymatic activity (oxidase). They are also particularlyimportant for the degradation (metabolism) of foreign substances such asdrugs or xenobiotics in mammalian organisms. The principalrepresentatives of the types and subtypes of CYP in the human body are:CYP 1A2, CYP 2C9, CYP 2D6 and CYP 3A4. If CYP 3A4 inhibitors (e.g.grapefruit juice, cimetidine, erythromycin) are used at the same time asmedicinal substances which are degraded by this enzyme system and thuscompete for the same binding site on the enzyme, the degradation thereofmay be slowed down and thus effects and side effects of the administeredmedicinal substance may be undesirably enhanced;

7.) a suitable solubility in water (in mg/ml);

8.) suitable pharmacokinetics (time course of the concentration of thecompound of the invention in plasma or in tissue, for example brain).The pharmacokinetics can be described by the following parameters:half-life (in h), volume of distribution (in l·kg⁻¹), plasma clearance(in l·h⁻¹·kg⁻¹), AUC (area under the curve, area under theconcentration-time curve, in ng·h·l⁻¹), oral bioavailability (thedose-normalized ratio of AUC after oral administration and AUC afterintravenous administration), the so-called brain-plasma ratio (the ratioof AUC in brain tissue and AUC in plasma);

9.) no or only low blockade of the hERG channel: compounds which blockthe hERG channel may cause a prolongation of the QT interval and thuslead to serious disturbances of cardiac rhythm (for example so-called“torsade de pointes”). The potential of compounds to block the hERGchannel can be determined by means of the displacement assay withradiolabelled dofetilide which is described in the literature (G. J.Diaz et al., Journal of Pharmacological and Toxicological Methods, 50(2004), 187-199). A smaller IC50 in this dofetilide assay means agreater probability of potent hERG blockade. Moreover, the blockade ofthe hERG channel can be measured by electrophysiological experiments oncells which have been transfected with the hERG channel, by so-calledwhole-cell patch clamping, as shown in the below assay (G. J. Diaz etal., Journal of Pharmacological and Toxicological Methods, 50 (2004),187-199). The higher the K_(i) values in the below assay (determined inthe unit “micromolar (μM)”), the lower the probability of potent hERGblockade.

One object of the present invention was to provide compounds which havea high affinity for the 5-HT₆ receptor. A further object of the presentinvention was to provide compounds which selectively bind to the 5-HT₆receptor [especially as mentioned above under 1.), 2.), 3.) and/or 4.)].In addition, the compounds of the invention should have one or more ofthe aforementioned advantages mentioned under 5.) to 9.) andspecifically under 5.) (metabolic stability).

The present invention provides compounds which have an affinity for the5-HT₆ receptor, thus allowing the treatment of disorders related to oraffected by the 5-HT₆ receptor.

SUMMARY OF THE INVENTION

The present invention relates to quinoline compounds which comprise anN-bound saturated heteromono- or -bicyclic ring containing one (and onlyone) nitrogen atom as ring member (the one via which the ring is bound),where this N-bound ring carries 1, 2 or 3 specific oxygen-containingsubstituents and where the ring is either bound in 8-position of thequinoline scaffold or is bound to the (hetero)aromatic ring in the3-position of the quinoline scaffold; to a pharmaceutical compositioncontaining such compounds, to such compounds for use as a medicament andto such compounds for use in the prevention or treatment of conditionsand disorders which respond to the modulation of 5-HT₆ receptor, totheir use as modulators of the 5-HT₆ receptor, to their use forpreparing a medicament for the prevention or treatment of conditions anddisorders which respond to the modulation of 5-HT₆ receptor, to methodsfor preventing or treating conditions and disorders which respond to themodulation of 5-HT₆ receptor, and to processes for preparing suchcompounds and compositions.

In one aspect, the present invention relates to compounds of the formulaI:

wherein

-   R¹ is selected from the group consisting of a ring R^(a), halogen,    C₁-C₂-haloalkyl, C₁-C₂-alkoxy, C₁-C₂-haloalkoxy, an N-bound    saturated 3-, 4-, 5-, 6-, 7- or 8-membered heteromonocyclic ring    containing one or two nitrogen atoms as ring members; and an N-bound    saturated 7-, 8-, 9-, 10-, 11- or 12-membered heterobicyclic ring    containing one or two nitrogen atoms as ring members; where the    heteromonocyclic ring and the heterobicyclic ring may carry one or    more substituents R⁴;-   R² is selected from the group consisting of a phenyl ring, a    naphthyl ring, a 5- or 6-membered monocyclic heteroaromatic ring    containing 1, 2, 3 or 4 heteroatoms selected from the group    consisting of N, O and S as ring members, and a 9- or 10-membered    bicyclic heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms    selected from the group consisting of N, O and S as ring members,    where the phenyl, the naphthyl and the monocyclic or bicyclic    heteroaromatic ring may carry one ring R^(a) and/or one or more    substituents R⁵;

with the proviso that R¹ is R^(a) if the ring R² is not substituted byR^(a);

-   each R³ is independently selected from the group consisting of    halogen, cyano, nitro, hydroxyl, C₁-C₆-alkyl, C₁-C₆-haloalkyl,    C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₁-C₆-alkylthio,    C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,    C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,    C₁-C₆-alkylcarbonyl, C₁-C₆-haloalkylcarbonyl, C₁-C₆-alkoxycarbonyl,    C₁-C₆-haloalkoxycarbonyl, aminocarbonyl, C₁-C₆-alkylaminocarbonyl    and di-(C₁-C₆-alkyl)-aminocarbonyl;-   each R⁴ is independently selected from the group consisting of    halogen, cyano, nitro, C₁-C₆-alkyl, C₁-C₆-haloalkyl,    C₃-C₆-cycloalkyl, C₃-C₆-halocycloalkyl, C₁-C₆-alkylthio,    C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,    C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl and oxo;-   each R⁵ is independently selected from the group consisting of    halogen, cyano, nitro, hydroxyl, C₁-C₆-alkyl, C₁-C₆-haloalkyl,    C₃-C₆-cycloalkyl, C₃-C₆-halocycloalkyl, C₁-C₆-alkoxy,    C₁-C₆-haloalkoxy, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,    C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,    C₁-C₆-haloalkylsulfonyl, formyl, C₁-C₆-alkylcarbonyl,    C₁-C₆-haloalkylcarbonyl, carboxyl, carboxyl-C₁-C₂-alkyl,    C₁-C₆-alkoxycarbonyl, C₁-C₆-haloalkoxycarbonyl, amino,    C₁-C₆-alkylamino, di-(C₁-C₆-alkyl)-amino, aminocarbonyl,    C₁-C₆-alkylaminocarbonyl, di-(C₁-C₆-alkyl)-aminocarbonyl, phenyl    which may carry one or more substituents R⁶; and a 3-, 4-, 5-, 6-,    7- or 8-membered saturated, partially unsaturated or maximally    unsaturated heterocyclic ring containing 1, 2 or 3 heteroatoms or    heteroatom groups selected from the group consisting of N, O, S, NO,    S(O) and S(O)₂ as ring members, where the heterocyclic ring may    carry one or more substituents R⁷;-   each R⁶ is independently selected from the group consisting of    halogen, cyano, nitro, hydroxyl, C₁-C₆-alkyl, C₁-C₆-haloalkyl,    C₃-C₆-cycloalkyl, C₃-C₆-halocycloalkyl, C₁-C₆-alkoxy,    C₁-C₆-haloalkoxy, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,    C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,    C₁-C₆-haloalkylsulfonyl, formyl, C₁-C₆-alkylcarbonyl,    C₁-C₆-haloalkylcarbonyl, carboxyl, carboxyl-C₁-C₂-alkyl,    C₁-C₆-alkoxycarbonyl, C₁-C₆-haloalkoxycarbonyl, amino,    C₁-C₆-alkylamino, di-(C₁-C₆-alkyl)-amino, and —C(O)N(R)R⁹;-   each R⁷ is independently selected from the group consisting of    halogen, cyano, nitro, C₁-C₆-alkyl, C₁-C₆-haloalkyl,    C₃-C₆-cycloalkyl, C₃-C₆-halocycloalkyl, C₁-C₆-alkylthio,    C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,    C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,    C₁-C₆-alkylcarbonyl, C₁-C₆-haloalkylcarbonyl, C₁-C₆-alkoxycarbonyl,    C₁-C₆-haloalkoxycarbonyl, amino, C₁-C₆-alkylamino and    di-(C₁-C₆-alkyl)-amino;-   R⁸ and R⁹, independently of each other and independently of each    occurrence, are selected from the group consisting of hydrogen,    C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl,    C₃-C₆-halocycloalkyl, C₃-C₆-cycloalkyl-C₁-C₄-alkyl,    C₃-C₆-halocycloalkyl-C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,    phenyl and benzyl; or    -   R⁸ and R⁹, together with the nitrogen atom they are bound to,        form a 3-, 4-, 5-, 6-7- or 8-membered saturated heterocyclic        ring which may contain 1, 2 or 3 additional heteroatoms or        heteroatom groups selected from the group consisting of N, O, S,        NO, S(O) and S(O)₂; where the ring may carry 1, 2 or 3        substituents selected from the group consisting of halogen,        cyano, nitro, hydroxyl, C₁-C₆-alkyl, C₁-C₆-haloalkyl,        C₃-C₆-cycloalkyl, C₃-C₆-halocycloalkyl, C₁-C₆-alkoxy,        C₁-C₆-haloalkoxy, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,        C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,        C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,        C₁-C₆-alkylcarbonyl, C₁-C₆-haloalkylcarbonyl, carboxyl,        C₁-C₆-alkoxycarbonyl and C₁-C₆-haloalkoxycarbonyl;-   L is a S(O)₂, CH₂—S(O)₂, S(O)₂—CH₂, C(O)—NH, NH—C(O) NH—S(O)₂ or    S(O)₂—NH;-   R^(a) is an N-bound saturated 3-, 4-, 5-, 6-, 7- or 8-membered    heteromonocyclic ring containing one (and only one) nitrogen atom as    ring member (which is the nitrogen atom via which this ring is    bound); or an N-bound saturated 7-, 8-, 9-, 10-, 11- or 12-membered    heterobicyclic ring containing one (and only one) nitrogen atom as    ring member (which is the nitrogen atom via which this ring is    bound), where the heteromonocyclic or heterobicyclic ring carries 1,    2 or 3 substituents R^(b) and optionally 1 or 2 further substituents    R⁴;-   R^(b) is an oxygen-containing radical independently selected from    the group consisting of hydroxyl, C₁-C₄-alkoxy, —C(O)OH, —CH₂—C(O)OH    and —C(O)N(R⁸)R⁹; and-   m is 0, 1 or 2;    and the N-oxides, tautomeric forms, stereoisomers and    pharmaceutically acceptable salts thereof; and the compound of the    general formula I, wherein at least one of the atoms has been    replaced by its stable, non-radioactive isotope.

In another aspect, the invention relates to a pharmaceutical compositioncomprising a therapeutically effective amount of at least one compoundof formula I or an N-oxide, a tautomeric form, a stereoisomer or apharmaceutically acceptable salt thereof, or a compound of the generalformula I, wherein at least one of the atoms has been replaced by itsstable, non-radioactive isotope, in combination with at least onepharmaceutically acceptable carrier and/or auxiliary substance.

In yet another aspect, the invention relates to a compound of formula Ior an N-oxide, a tautomeric form, a stereoisomer or a pharmaceuticallyacceptable salt thereof or a compound of the general formula I, whereinat least one of the atoms has been replaced by its stable,non-radioactive isotope, for use as a medicament.

In yet another aspect, the invention relates to a compound of formula Ior an N-oxide, a tautomeric form, a stereoisomer or a pharmaceuticallyacceptable salt thereof or a compound of the general formula I, whereinat least one of the atoms has been replaced by its stable,non-radioactive isotope, for use in the treatment of disorders whichrespond to the modulation of the 5-HT₆ receptor.

In yet another aspect, the invention relates to a compound of formula Ior an N-oxide, a tautomeric form, a stereoisomer or a pharmaceuticallyacceptable salt thereof or a compound of the general formula I, whereinat least one of the atoms has been replaced by its stable,non-radioactive isotope, for use in the treatment of disorders selectedfrom the group consisting of disorders and diseases of the centralnervous system, in particular cognitive dysfunctions, such as a deficitin memory, cognition and learning, in particular associated withAlzheimer's disease, age-related cognitive decline and mild cognitiveimpairment, attention deficit disorder/hyperactivity syndrome (ADHD),personality disorders, such as schizophrenia, in particular cognitivedeficits related with schizophrenia, affective disorders such asdepression, anxiety and obsessive compulsive disorders, motion or motordisorders such as Parkinson's disease and epilepsy, migraine, sleepdisorders (including disturbances of the Circadian rhythm), feedingdisorders, such as anorexia and bulimia, certain gastrointestinaldisorders such as Irritable Bowel Syndrome, diseases associated withneurodegeneration, such as stroke, spinal or head trauma and headinjuries, including hydrocephalus, addiction, in particular drugaddiction, and obesity.

In yet another aspect, the invention relates to the use of a compound offormula I or of an N-oxide, a tautomeric form, a stereoisomer or apharmaceutically acceptable salt thereof or a compound of the generalformula I, wherein at least one of the atoms has been replaced by itsstable, non-radioactive isotope, for the manufacture of a medicament forthe treatment of disorders which respond to the modulation of the 5-HT₆receptor.

In yet another aspect, the invention relates to the use of a compound offormula I or of an N-oxide, a stereoisomer or a pharmaceuticallyacceptable salt thereof or a compound of the general formula I, whereinat least one of the atoms has been replaced by its stable,non-radioactive isotope, for the manufacture of a medicament for thetreatment of disorders selected from the group consisting of disordersand diseases of the central nervous system, in particular cognitivedysfunctions, such as a deficit in memory, cognition and learning, inparticular associated with Alzheimer's disease, age-related cognitivedecline and mild cognitive impairment, attention deficitdisorder/hyperactivity syndrome (ADHD), personality disorders, such asschizophrenia, in particular cognitive deficits related withschizophrenia, affective disorders such as depression, anxiety andobsessive compulsive disorders, motion or motor disorders such asParkinson's disease and epilepsy, migraine, sleep disorders (includingdisturbances of the Circadian rhythm), feeding disorders, such asanorexia and bulimia, certain gastrointestinal disorders such asIrritable Bowel Syndrome, diseases associated with neurodegeneration,such as stroke, spinal or head trauma and head injuries, includinghydrocephalus, addiction, in particular drug addiction, and obesity.

In yet another aspect, the invention relates to a method for treatingdisorders which respond to the modulation of the 5-HT₆ receptor, whichmethod comprises administering to a subject in need thereof at least onecompound of formula I or an N-oxide, a tautomeric form, a stereoisomeror a pharmaceutically acceptable salt thereof or a compound of thegeneral formula I, wherein at least one of the atoms has been replacedby its stable, non-radioactive isotope.

In yet another aspect, the invention relates to a method for treatingdisorders selected from the group consisting of disorders and diseasesof the central nervous system, in particular cognitive dysfunctions,such as a deficit in memory, cognition and learning, in particularassociated with Alzheimer's disease, age-related cognitive decline andmild cognitive impairment, attention deficit disorder/hyperactivitysyndrome (ADHD), personality disorders, such as schizophrenia, inparticular cognitive deficits related with schizophrenia, affectivedisorders such as depression, anxiety and obsessive compulsivedisorders, motion or motor disorders such as Parkinson's disease andepilepsy, migraine, sleep disorders (including disturbances of theCircadian rhythm), feeding disorders, such as anorexia and bulimia,certain gastrointestinal disorders such as Irritable Bowel Syndrome,diseases associated with neurodegeneration, such as stroke, spinal orhead trauma and head injuries, including hydrocephalus, addiction, inparticular drug addiction, and obesity, which method comprisesadministering to a subject in need thereof at least one compound offormula I or an N-oxide, a tautomeric form, a stereoisomer or apharmaceutically acceptable salt thereof or a compound of the generalformula I, wherein at least one of the atoms has been replaced by itsstable, non-radioactive isotope.

DETAILED DESCRIPTION

The proviso that R¹ is R^(a) if the ring R² is not substituted by R^(a)means that either R¹ is R^(a) and R² can have any of the abovedefinitions, or R² is a phenyl, naphthyl or a monocyclic or bicyclicheteroaromatic ring as defined above which carries a ring R^(a) (andoptionally one or more substituents R⁵) and R¹ can have any of the abovedefinitions. As can be understood from the above, it is of coursepossible that R¹ is R^(a) and simultaneously the phenyl, naphthyl orheteroaromatic ring R² carries a ring R^(a). The compounds of theformula I may exist in different spatial arrangements, for example ifthey possess one or more centers of asymmetry, polysubstituted rings ordouble bonds. The invention relates to enantiomeric mixtures, inparticular racemates, diastereomeric mixtures, as well as to therespective essentially pure enantiomers and diastereomers of thecompounds of formula I and/or of their salts and/or their N-oxidesand/or their tautomeric forms and/or their prodrugs and/or of compoundsof the formula I, wherein at least one of the atoms has been replaced byits stable, non-radioactive isotope.

For instance, rings R^(a) can contain one or more centers of asymmetry.If this ring has no rotary reflexion axis and does not carry twogeminally bound, identical substituents R^(b) and/or two geminallybound, identical substituents R⁴—in other words if ring R^(a) is notpresent in meso form—compounds I may be present in form of differentenantiomers, diastereomers or enantiomeric or diastereomeric mixtures.

In the terms of the present invention, “prodrugs” are compounds whichare metabolized in vivo to give the compounds of the invention offormula I. Typical examples for prodrugs are for example described in C.G. Wermeth (editor): The Practice of Medicinal Chemistry, AcademicPress, San Diego, 1996, pages 671-715. Examples are phosphates,carbamates, aminoacids, esters, amides, peptides, urea and the like. Inthe present case, suitable prodrugs can be compounds of formula Iwherein a primary or secondary nitrogen atom, for example the nitrogenatom of an amino or C₁-C₆-alkylamino group R⁵, R⁶ or R⁷ or a secondarynitrogen atom of a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partiallyunsaturated or maximally unsaturated heterocyclic ring R⁵ or a secondarynitrogen atom of an N-bound saturated 3-, 4-, 5-, 6-, 7- or 8-memberedheteromonocyclic ring R¹ containing two nitrogen atoms as ring membersor of an N-bound saturated 7-, 8-, 9-, 19-, 11- or 12-memberedheterobicyclic ring R¹ containing two nitrogen atoms as ring members,forms an amide/peptide bond in that this nitrogen atom is substituted bya C₁-C₄-alkylcarbonyl group, e.g. by acetyl, propionyl,n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl ortert-butylcarbonyl (pivaloyl), by benzoyl, or by an aminoacid groupbonded via CO, e.g. glycine, alanine, serine, phenylalanine and the likebonded via CO. Suitable prodrugs are furthermorealkylcarbonyloxyalkylcarbamates, wherein said nitrogen atom carries agroup —C(═O)—O—CHR^(x)—O—C(═O)—R^(y), wherein R^(x) und R^(y)independently of each other are C₁-C₄-alkyl. These carbamate compoundsare for example described in J. Alexander, R. Cargill, S. R. Michelson,H. Schwam, J. Medicinal Chem. 1988, 31(2), 318-322.

In other words, prodrugs of compounds I are for example:

compounds I in which one of R⁵, R⁶ or R⁷ is —NHR or —N(C₁-C₆-alkyl)R,where R is C₁-C₄-alkylcarbonyl, in particular acetyl, propionyl,n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl ortert-butylcarbonyl (pivaloyl), or R is benzoyl, or R is an aminoacidgroup bonded via CO, in particular a glycine, alanine, serine orphenylalanine residue bonded via CO, or R is—C(═O)—O—CHR^(x)—O—C(═O)—R^(y), wherein R^(x) und R^(y) independently ofeach other are C₁-C₄-alkyl; or are

compounds I in which at least one R⁵ is a 3-, 4-, 5-, 6-, 7- or8-membered saturated, partially unsaturated or maximally unsaturatedheterocyclic ring containing 1, 2 or 3 heteroatoms or heteroatom groupsselected from the group consisting of N, O, S, NO, S(O) and S(O)₂ asring members, where at least one of these heteroatoms or heteroatomgroups is a group NR, where R is C₁-C₄-alkylcarbonyl, in particularacetyl, propionyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonylor tert-butylcarbonyl (pivaloyl), or R is benzoyl, or R is an aminoacidgroup bonded via CO, in particular a glycine, alanine, serine orphenylalanine residue bonded via CO, or R is—C(═O)—O—CHR^(x)—O—C(═O)—R^(y), wherein R^(x) und R^(y) independently ofeach other are C₁-C₄-alkyl, where the heterocyclic ring may additionallycarry one or more substituents R⁷;

or are compounds I in which R¹ is an N-bound saturated 3-, 4-, 5-, 6-,7- or 8-membered heteromonocyclic ring R¹ containing two nitrogen atomsas ring members or is an N-bound saturated 7-, 8-, 9-, 10-, 11- or12-membered heterobicyclic ring R¹ containing two nitrogen atoms as ringmembers, where the second nitrogen atom in this heteromono- or -bicyclicring via which the ring is not bound to the quinoline scaffold ispresent as a group NR, where R is C₁-C₄-alkylcarbonyl, in particularacetyl, propionyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonylor tert-butylcarbonyl (pivaloyl), or R is benzoyl, or R is an aminoacidgroup bonded via CO, in particular a glycine, alanine, serine orphenylalanine residue bonded via CO, or R is—C(═O)—O—CHR^(x)—O—C(═O)—R^(y), wherein R^(x) und R^(y) independently ofeach other are C₁-C₄-alkyl; where the heteromonocyclic ring and theheterobicyclic ring may additionally carry one or more substituents R⁴.

These groups can be removed under metabolic conditions and result incompounds of formula I, wherein said nitrogen atom carries a hydrogenatom instead.

The invention also relates to N-oxides of the compounds of the formulaI, provided that those compounds contain a basic nitrogen atom, such asthe nitrogen atom of the quinoline ring or of various heterocyclicmoieties R¹, R² and R⁵ containing at least one basic nitrogen atom asring member.

The invention also relates to tautomeric forms of the compounds of theformula I, present e.g. in compounds I containing amide groups orlactame groups or in which an OH group is bound to a C—C or C—N doublebond. Under given conditions, one tautomeric form often predominates,but as the transition of one tautomeric form to another is generally anequilibrium reaction, the presence of the non-favoured form cangenerally not be excluded.

It is likewise possible to use physiologically tolerated salts of thecompounds of the formula I, especially acid addition salts withphysiologically tolerated acids. Examples of suitable physiologicallytolerated organic and inorganic acids are hydrochloric acid, hydrobromicacid, phosphoric acid, sulfuric acid, acetic acid, trifluoroacetic acid,C₁-C₄-alkylsulfonic acids, such as methanesulfonic acid, aromaticsulfonic acids, such as benzenesulfonic acid and toluenesulfonic acid,oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid,adipic acid and benzoic acid. Other utilizable acids are described inFortschritte der Arzneimittelforschung [Advances in drug research],Volume 10, pages 224 et seq., Birkhäuser Verlag, Basel and Stuttgart,1966.

The organic moieties mentioned in the above definitions of the variablesare, like the term halogen, collective terms for individual listings ofthe individual group members. The prefix C_(n)-C_(m) indicates in eachcase the possible number of carbon atoms in the group.

The term “halogen” denotes in each case fluorine, bromine, chlorine oriodine. In one aspect, the halogen may be fluorine, chlorine or bromine.

The term “alkyl” as used herein and in the alkyl moieties of alkoxy andthe like refers to saturated straight-chain or branched hydrocarbonradicals having 1 to 2 (“C₁-C₂-alkyl”), 1 to 3 (“C₁-C₃-alkyl”), 1 to 4(“C₁-C₄-alkyl”) or 1 to 6 (“C₁-C₆-alkyl”) carbon atoms. C₁-C₂-Alkyl ismethyl or ethyl. Examples for C₁-C₃-alkyl are, in addition to thosementioned for C₁-C₂-alkyl, propyl and isopropyl. Examples forC₁-C₄-alkyl are, in addition to those mentioned for C₁-C₃-alkyl, butyl,1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl) or1,1-dimethylethyl (tert-butyl). Examples for C₁-C₆-alkyl are, inaddition to those mentioned for C₁-C₄-alkyl, pentyl, 1-methylbutyl,2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, hexyl, 1-methylpentyl,2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl,2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl,1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, or1-ethyl-2-methylpropyl.

The term “fluorinated alkyl” as used herein refers to straight-chain orbranched alkyl groups having 1 to 2 (“fluorinated C₁-C₂-alkyl”), 1 to 3(“fluorinated C₁-C₃-alkyl”), 1 to 4 (“fluorinated C₁-C₄-alkyl”) or 1 to6 (“fluorinated C₁-C₆-alkyl”) carbon atoms (as mentioned above), wheresome or all of the hydrogen atoms in these groups are replaced byfluorine atoms. Fluorinated methyl is fluoromethyl (CH₂F),difluoromethyl (CHF₂) or trifluoromethyl (CF₃). Fluorinated C₁-C₂-alkylis an alkyl group having 1 or 2 carbon atoms (as mentioned above), whereat least one of the hydrogen atoms, e.g. 1, 2, 3, 4 or 5 hydrogen atomsin these groups are replaced by fluorine atoms, such as fluoromethyl,difluoromethyl, trifluoromethyl, 1-fluoroethyl, (R)-1-fluoroethyl,(S)-1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, or pentafluoroethyl. Fluorinated C₁-C₃-alkyl is astraight-chain or branched alkyl group having 1 to 3 carbon atoms (asmentioned above), where at least one of the hydrogen atoms, e.g. 1, 2,3, 4 or 5 hydrogen atoms in these groups are replaced by fluorine atoms.Examples are, in addition to those listed above for fluorinatedC₁-C₂-alkyl, 1-fluoropropyl, (R)-1-fluoropropyl, (S)-1-fluoropropyl,2-fluoropropyl, (R)-2-fluoropropyl, (S)-2-fluoropropyl, 3-fluoropropyl,1,1-difluoropropyl, 2,2-difluoropropyl, 1,2-difluoropropyl,2,3-difluorropopyl, 1,3-difluoropropyl, 3,3-difluoropropyl,1,1,2-trifluoropropyl, 1,2,2-trifluoropropyl, 1,2,3-trifluoropropyl,2,2,3-trifluoropropyl, 3,3,3-trifluoropropyl, 1,1,1-trifluoroprop-2-yl,2-fluoro-1-methylethyl, (R)-2-fluoro-1-methylethyl,(S)-2-fluoro-1-methylethyl, 2,2-difluoro-1-methylethyl,(R)-2,2-difluoro-1-methylethyl, (S)-2,2-difluoro-1-methylethyl,1,2-difluoro-1-methylethyl, (R)-1,2-difluoro-1-methylethyl,(S)-1,2-difluoro-1-methylethyl, 2,2,2-trifluoro-1-methylethyl,(R)-2,2,2-trifluoro-1-methylethyl, (S)-2,2,2-trifluoro-1-methylethyl,2-fluoro-1-(fluoromethyl)ethyl, 1-(difluoromethyl)-2,2-difluoroethyl,1-(trifluoromethyl)-2,2,2-trifluoroethyl and1-(trifluoromethyl)-1,2,2,2-tetrafluoroethyl. Fluorinated C₁-C₄-alkyl isa straight-chain or branched alkyl group having 1 to 4 carbon atoms (asmentioned above), where at least one of the hydrogen atoms, e.g. 1, 2,3, 4 or 5 hydrogen atoms in these groups are replaced by fluorine atoms.Examples are, in addition to those listed above for fluorinatedC₁-C₃-alkyl, 1-fluorobutyl, (R)-1-fluorobutyl, (S)-1-fluorobutyl,2-fluorobutyl, (R)-2-fluorobutyl, (S)-2-fluorobutyl, 3-fluorobutyl,(R)-3-fluorobutyl, (S)-3-fluorobutyl, 4-fluorobutyl, 1,1-difluorobutyl,2,2-difluorobutyl, 3,3-difluorobutyl, 4,4-difluorobutyl,4,4,4-trifluorobutyl and the like. Fluorinated C₁-C₆-alkyl is astraight-chain or branched alkyl group having 1 to 6 carbon atoms (asmentioned above), where at least one of the hydrogen atoms, e.g. 1, 2,3, 4 or 5 hydrogen atoms in these groups are replaced by fluorine atoms.Examples are, in addition to those listed above for fluorinatedC₁-C₄-alkyl, 1-fluoropentyl, (R)-1-fluoropentyl, (S)-1-fluoropentyl,2-fluoropentyl, (R)-2-fluoropentyl, (S)-2-fluoropentyl, 3-fluoropentyl,(R)-3-fluoropentyl, (S)-3-fluoropentyl, 4-fluoropentyl,(R)-4-fluoropentyl, (S)-4-fluoropentyl, 5-fluoropentyl,(R)-5-fluoropentyl, (S)-5-fluoropentyl, 1-fluorohexyl,(R)-1-fluorohexyl, (S)-1-fluorohexyl, 2-fluorohexyl, (R)-2-fluorohexyl,(S)-2-fluorohexyl, 3-fluorohexyl, (R)-3-fluorohexyl, (S)-3-fluorohexyl,4-fluorohexyl, (R)-4-fluorohexyl, (S)-4-fluorohexyl, 5-fluorohexyl,(R)-5-fluorohexyl, (S)-5-fluorohexyl, 6-fluorohexyl, (R)-6-fluorohexyl,(S)-6-fluorohexyl, and the like. Fluorinated C₁-C₈-alkyl is astraight-chain or branched alkyl group having 1 to 8 carbon atoms (asmentioned above), where at least one of the hydrogen atoms, e.g. 1, 2,3, 4 or 5 hydrogen atoms in these groups are replaced by fluorine atoms.

The term “haloalkyl” as used herein, which may also be expressed as“alkyl which is partially or fully halogenated”, refers tostraight-chain or branched alkyl groups having 1 to 2(“C₁-C₂-haloalkyl”), 1 to 3 (“C₁-C₃-haloalkyl”), 1 to 4(“C₁-C₄-haloalkyl”) or 1 to 4 (“C₁-C₆-haloalkyl”) carbon atoms (asmentioned above), where some or all of the hydrogen atoms in thesegroups are replaced by halogen atoms as mentioned above. Examples forC₁-C₂-haloalkyl are, in addition to those listed above for fluorinatedC₁-C₂-alkyl, chloromethyl, bromomethyl, dichloromethyl, trichloromethyl,chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl,1-chloroethyl, 1-bromoethyl, 2-chloro-2-fluoroethyl,2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl or2,2,2-trichloroethyl. Examples for C₁-C₃-haloalkyl are, in addition tothose listed above for C₁-C₂-haloalkyl and for fluorinated C₁-C₃-alkyl,3-chloropropyl and the like. Examples for C₁-C₄-haloalkyl are, inaddition to those mentioned above for C₁-C₃-haloalkyl and forfluorinated C₁-C₄-alkyl, 4-chlorobutyl and the like. Examples forC₁-C₆-haloalkyl are, in addition to those mentioned above forC₁-C₄-haloalkyl and for fluorinated C₁-C₆-alkyl, 5-chloropentyl,6-chlorohexyl and the like.

The term “cycloalkyl” as used herein refers to monocyclic saturatedhydrocarbon radicals having 3 to 6 carbon atoms (“C₃-C₆-cycloalkyl”).Examples of C₃-C₆-cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyland cyclohexyl.

The term “halocycloalkyl” as used herein refers to monocyclic saturatedhydrocarbon groups having 3 to 6 (“C₃-C₆-halocycloalkyl”) carbon ringmembers (as mentioned above) in which some or all of the hydrogen atomsare replaced by halogen atoms. Examples are 1-fluorocyclopropyl,2-fluorocyclopropyl, (S)- and (R)-2,2-difluorocyclopropyl,1,2-difluorocyclopropyl, 2,3-difluorocyclopropyl,pentafluorocyclopropyl, 1-chlorocyclopropyl, 2-chlorocyclopropyl,2,3-dichlorocyclopropyl, 2-chloro-1-fluorocyclopropyl,3-chloro-2-fluorocyclopropyl, 2-bromocyclopropyl, 1-fluorocyclobutyl,2-fluorocyclobutyl, 3-fluorocyclobutyl, 2,2-difluorocyclobutyl,3,3-difluorocyclobutyl, 1,2-difluorocyclobutyl, 1,3-difluorocyclobutyl,2,3-difluorocyclobutyl, 2,4-difluorocyclobutyl,1,2,2-trifluorocyclobutyl, 1-chlorocyclobutyl, 2-chlorocyclobutyl,3-chlorocyclobutyl, 2,2-dichlorocyclobutyl, 2,3-dichlorocyclobutyl,3,3-dichlorocyclobutyl, 2-bromocyclobutyl, 3-bromocyclobutyl,1-fluorocyclopentyl, 2-fluorocyclopentyl, 1,2-difluorocyclopentyl,1,3-difluorocyclopentyl, 2,2-difluorocyclopentyl,2,3-difluorocyclopentyl, 2,4-difluorocyclopentyl,2,5-difluorocyclopentyl, 3,3-difluorocyclopentyl,3,4-difluorocyclopentyl, 1-chlorocyclopentyl, 2-chlorocyclopentyl,3-chlorocyclopentyl, 1-fluorocyclohexyl, 2-fluorocyclohexyl,3-fluorocyclohexyl, 4-fluorocyclohexyl, 1,2-difluorocyclohexyl,1,3-difluorocyclohexyl, 1,4-difluorocyclohexyl, 2,2-difluorocyclohexyl,2,3-difluorocyclohexyl, 2,4-difluorocyclohexyl, 2,5-difluorocyclohexyl,2,6-difluorocyclohexyl, 3,3-difluorocyclohexyl, 3,4-difluorocyclohexyl,3,5-difluorocyclohexyl, 4,4-difluorocyclohexyl, 1-chlorocyclohexyl,2-chlorocyclohexyl, 3-chlorocyclohexyl, 4-chlorocyclohexyl, and thelike.

The term “C₃-C₆-cycloalkyl-C₁-C₄-alkyl” refers to a C₃-C₆-cycloalkylgroup, as defined above, which is bound to the remainder of the moleculevia a C₁-C₄-alkyl group, as defined above. Examples forC₃-C₄-cycloalkyl-C₁-C₄-alkyl are cyclopropylmethyl, cyclopropylethyl,cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl andcyclobutylpropyl, Examples for C₃-C₆-cycloalkyl-C₁-C₄-alkyl are, inaddition to those mentioned for C₃-C₄-cycloalkyl-C₁-C₄-alkyl,cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl,cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl and the like.

The term “C₃-C₆-halocycloalkyl-C₁-C₄-alkyl” refers to aC₃-C₆-halocycloalkyl group, as defined above, which is bound to theremainder of the molecule via a C₁-C₄-alkyl group, as defined above.

“C₁-C₂-Alkoxy” is a C₁-C₂-alkyl group, as defined above, attached via anoxygen atom to the remainder of the molecule. “C₁-C₃-Alkoxy” is aC₁-C₃-alkyl group, as defined above, attached via an oxygen atom to theremainder of the molecule. “C₁-C₄-Alkoxy” is a C₁-C₄-alkyl group, asdefined above, attached via an oxygen atom to the remainder of themolecule. “C₁-C₆-Alkoxy” is a C₁-C₆-alkyl group, as defined above,attached via an oxygen atom to the remainder of the molecule.C₁-C₂-Alkoxy is methoxy or ethoxy. Examples for C₁-C₃-alkoxy are, inaddition to those mentioned for C₁-C₂-alkoxy, n-propoxy and1-methylethoxy (isopropoxy). Examples for C₁-C₄-alkoxy are, in additionto those mentioned for C₁-C₃-alkoxy, butoxy, 1-methylpropoxy(sec-butoxy), 2-methylpropoxy (isobutoxy) or 1,1-dimethylethoxy(tert-butoxy). Examples for C₁-C₆-alkoxy are, in addition to thosementioned for C₁-C₄-alkoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy,3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy,2,2-dimethylpropoxy, 1-ethylpropoxy, hexoxy, 1-methylpentoxy,2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy,1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy,2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy,1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxyor 1-ethyl-2-methylpropoxy.

“C₁-C₂-Haloalkoxy” is a C₁-C₂-haloalkyl group, as defined above,attached via an oxygen atom to the remainder of the molecule.“C₁-C₃-Halolkoxy” is a C₁-C₃-haloalkyl group, as defined above, attachedvia an oxygen atom to the remainder of the molecule. “C₁-C₄-Haloalkoxy”is a C₁-C₄-haloalkyl group, as defined above, attached via an oxygenatom to the remainder of the molecule. “C₁-C₆-Haloalkoxy” is aC₁-C₆-haloalkyl group, as defined above, attached via an oxygen atom tothe remainder of the molecule. C₁-C₂-Haloalkoxy is, for example, OCH₂F,OCHF₂, OCF₃, OCH₂Cl, OCHCl₂, OCCl₃, chlorofluoromethoxy,dichlorofluoromethoxy, chlorodifluoromethoxy, 2-fluoroethoxy,2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2,2-difluoroethoxy,2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy,2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy,2,2,2-trichloroethoxy or OC₂F₅. Examples for C₁-C₃-haloalkoxy are, inaddition to those mentioned for C₁-C₂-haloalkoxy, 2-fluoropropoxy,3-fluoropropoxy, 2,2-difluoropropoxy, 2,3-difluoropropoxy,2-chloropropoxy, 3-chloropropoxy, 2,3-dichloropropoxy, 2-bromopropoxy,3-bromopropoxy, 3,3,3-trifluoropropoxy, 3,3,3-trichloropropoxy,OCH₂—C₂Fs, OCF₂—C₂Fs, 1-(CH₂F)-2-fluoroethoxy, 1-(CH₂Cl)-2-chloroethoxyor 1-(CH₂Br)-2-bromoethoxy. Examples for C₁-C₄-haloalkoxy are, inaddition to those mentioned for C₁-C₃-haloalkoxy, 4-fluorobutoxy,4-chlorobutoxy, 4-bromobutoxy or nonafluorobutoxy. Examples forC₁-C₆-haloalkoxy are, in addition to those mentioned forC₁-C₄-haloalkoxy, 5-fluoropentoxy, 5-chloropentoxy, 5-brompentoxy,5-iodopentoxy, undecafluoropentoxy, 6-fluorohexoxy, 6-chlorohexoxy,6-bromohexoxy, 6-iodohexoxy or dodecafluorohexoxy.

“C₁-C₂-Alkylthio” is a C₁-C₂-alkyl group, as defined above, attached viaa sulfur atom to the remainder of the molecule. “C₁-C₃-Alkylthio” is aC₁-C₃-alkyl group, as defined above, attached via a sulfur atom to theremainder of the molecule. “C₁-C₄-Alkylthio” is a C₁-C₄-alkyl group, asdefined above, attached via a sulfur atom to the remainder of themolecule. “C₁-C₆-Alkylthio” is a C₁-C₆-alkyl group, as defined above,attached via a sulfur atom to the remainder of the molecule.C₁-C₂-Alkylthio is methylthio or ethylthio. Examples for C₁-C₃-alkylthioare, in addition to those mentioned for C₁-C₂-alkylthio, n-propylthio or1-methylethylthio (isopropylthio).

Examples for C₁-C₄-alkylthio are, in addition to those mentioned forC₁-C₃-alkylthio, butylthio, 1-methylpropylthio (sec-butylthio),2-methylpropylthio (isobutylthio) or 1,1-dimethylethylthio(tert-butylthio). Examples for C₁-C₆-alkylthio are, in addition to thosementioned for C₁-C₄-alkylthio, pentylthio, 1-methylbutylthio,2-methylbutylthio, 3-methylbutylthio, 1,1-dimethylpropylthio,1,2-dimethylpropylthio, 2,2-dimethylpropylthio, 1-ethylpropylthio,hexylthio, 1-methylpentylthio, 2-methylpentylthio, 3-methylpentylthio,4-methylpentylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio,1,3-dimethylbutylthio, 2,2-dimethylbutylthio, 2,3-dimethylbutylthio,3,3-dimethylbutylthio, 1-ethylbutylthio, 2-ethylbutylthio,1,1,2-trimethylpropylthio, 1,2,2-trimethylpropylthio,1-ethyl-1-methylpropylthio or 1-ethyl-2-methylpropylthio.

“C₁-C₂-Haloalkylthio” is a C₁-C₂-haloalkyl group, as defined above,attached via a sulfur atom to the remainder of the molecule.“C₁-C₃-Haloalkylthio” is a C₁-C₃-haloalkyl group, as defined above,attached via a sulfur atom to the remainder of the molecule.“C₁-C₄-Haloalkylthio” is a C₁-C₄-haloalkyl group, as defined above,attached via a sulfur atom to the remainder of the molecule.“C₁-C₆-Haloalkylthio” is a C₁-C₆-haloalkyl group, as defined above,attached via a sulfur atom to the remainder of the molecule.C₁-C₂-Haloalkylthio is, for example, SCH₂F, SCHF₂, SCF₃, SCH₂Cl, SCHCl₂,SCCl₃, chlorofluoromethylthio, dichlorofluoromethylthio,chlorodifluoromethylthio, 2-fluoroethylthio, 2-chloroethylthio,2-bromoethylthio, 2-iodoethylthio, 2,2-difluoroethylthio,2,2,2-trifluoroethylthio, 2-chloro-2-fluoroethylthio,2-chloro-2,2-difluoroethylthio, 2,2-dichloro-2-fluoroethylthio,2,2,2-trichloroethylthio or SC₂F₅. C₁-C₃-Haloalkylthio is additionally,for example, 2-fluoropropylthio, 3-fluoropropylthio,2,2-difluoropropylthio, 2,3-difluoropropylthio, 2-chloropropylthio,3-chloropropylthio, 2,3-dichloropropylthio, 2-bromopropylthio,3-bromopropylthio, 3,3,3-trifluoropropylthio, 3,3,3-trichloropropylthio,SCH₂—C₂F₅, SCF₂—C₂F₅, 1-(CH₂F)-2-fluoroethylthio,1-(CH₂Cl)-2-chloroethylthio or 1-(CH₂Br)-2-bromoethylthio.C₁-C₄-Haloalkylthio is additionally, for example, 4-fluorobutylthio,4-chlorobutylthio, 4-bromobutylthio or nonafluorobutylthio.C₁-C₆-Haloalkylthio is additionally, for example, 5-fluoropentylthio,5-chloropentylthio, 5-brompentylthio, 5-iodopentylthio,undecafluoropentylthio, 6-fluorohexylthio, 6-chlorohexylthio,6-bromohexylthio, 6-iodohexylthio or dodecafluorohexylthio.

“C₁-C₂-Alkylsulfinyl” is a C₁-C₂-alkyl group, as defined above, attachedvia a sulfinyl [S(O)] group to the remainder of the molecule.“C₁-C₃-Alkylsulfinyl” is a C₁-C₃-alkyl group, as defined above, attachedvia a sulfinyl [S(O)] group to the remainder of the molecule.“C₁-C₄-Alkylsulfinyl” is a C₁-C₄-alkyl group, as defined above, attachedvia a sulfinyl [S(O)] group to the remainder of the molecule.“C₁-C₆-Alkylsulfinyl” is a C₁-C₆-alkyl group, as defined above, attachedvia a sulfinyl [S(O)] group to the remainder of the molecule.C₁-C₂-Alkylsulfinyl is methylsulfinyl or ethylsulfinyl. Examples forC₁-C₃-alkylsulfinyl are, in addition to those mentioned forC₁-C₂-alkylsulfinyl, n-propylsulfinyl and 1-methylethylsulfinyl(isopropylsulfinyl). Examples for C₁-C₄-alkylsulfinyl are, in additionto those mentioned for C₁-C₃-alkylsulfinyl, butylsulfinyl,1-methylpropylsulfinyl (sec-butylsulfinyl), 2-methylpropylsulfinyl(isobutylsulfinyl) and 1,1-dimethylethylsulfinyl (tert-butylsulfinyl).Examples for C₁-C₆-alkylsulfinyl are, in addition to those mentioned forC₁-C₄-alkylsulfinyl, pentylsulfinyl, 1-methylbutylsulfinyl,2-methylbutylsulfinyl, 3-methylbutylsulfinyl,1,1-dimethylpropylsulfinyl, 1,2-dimethylpropylsulfinyl,2,2-dimethylpropylsulfinyl, 1-ethylpropylsulfinyl, hexylsulfinyl,1-methylpentylsulfinyl, 2-methylpentylsulfinyl, 3-methylpentylsulfinyl,4-methylpentylsulfinyl, 1,1-dimethylbutylsulfinyl,1,2-dimethylbutylsulfinyl, 1,3-dimethylbutylsulfinyl,2,2-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl,3,3-dimethylbutylsulfinyl, 1-ethylbutylsulfinyl, 2-ethylbutylsulfinyl,1,1,2-trimethylpropylsulfinyl, 1,2,2-trimethylpropylsulfinyl,1-ethyl-1-methylpropylsulfinyl or 1-ethyl-2-methylpropylsulfinyl.

“C₁-C₂-Haloalkylsulfinyl” is a C₁-C₂-haloalkyl group, as defined above,attached via a sulfinyl [S(O)] group to the remainder of the molecule.“C₁-C₃-Haloalkylsulfinyl” is a C₁-C₃-haloalkyl group, as defined above,attached via a sulfinyl [S(O)] group to the remainder of the molecule.“C₁-C₄-Haloalkylsulfinyl” is a C₁-C₄-haloalkyl group, as defined above,attached via a sulfinyl [S(O)] group to the remainder of the molecule.“C₁-C₆-Haloalkylsulfinyl” is a C₁-C₆-haloalkyl group, as defined above,attached via a sulfinyl [S(O)] group to the remainder of the molecule.C₁-C₂-Haloalkylsulfinyl is, for example, S(O)CH₂F, S(O)CHF₂, S(O)CF₃,S(O)CH₂Cl, S(O)CHCl₂, S(O)CC₃, chlorofluoromethylsulfinyl,dichlorofluoromethylsulfinyl, chlorodifluoromethylsulfinyl,2-fluoroethylsulfinyl, 2-chloroethylsulfinyl, 2-bromoethylsulfinyl,2-iodoethylsulfinyl, 2,2-difluoroethylsulfinyl,2,2,2-trifluoroethylsulfinyl, 2-chloro-2-fluoroethylsulfinyl,2-chloro-2,2-difluoroethylsulfinyl, 2,2-dichloro-2-fluoroethylsulfinyl,2,2,2-trichloroethylsulfinyl or S(O)C₂F₅. Examples forC₁-C₃-haloalkylsulfinyl are, in addition to those mentioned forC₁-C₂-haloalkylsulfinyl, 2-fluoropropylsulfinyl, 3-fluoropropylsulfinyl,2,2-difluoropropylsulfinyl, 2,3-difluoropropylsulfinyl,2-chloropropylsulfinyl, 3-chloropropylsulfinyl,2,3-dichloropropylsulfinyl, 2-bromopropylsulfinyl,3-bromopropylsulfinyl, 3,3,3-trifluoropropylsulfinyl,3,3,3-trichloropropylsulfinyl, S(O)CH₂—C₂Fs, S(O)CF₂—C₂Fs,1-(CH₂F)-2-fluoroethylsulfinyl, 1-(CH₂Cl)-2-chloroethylsulfinyl and1-(CH₂Br)-2-bromoethylsulfinyl. Examples for C₁-C₄-haloalkylsulfinylare, in addition to those mentioned for C₁-C₃-haloalkylsulfinyl,4-fluorobutylsulfinyl, 4-chlorobutylsulfinyl, 4-bromobutylsulfinyl ornonafluorobutylsulfinyl. Examples for C₁-C₆-haloalkylsulfinyl are, inaddition to those mentioned for C₁-C₄-haloalkylsulfinyl,5-fluoropentylsulfinyl, 5-chloropentylsulfinyl, 5-brompentylsulfinyl,5-iodopentylsulfinyl, undecafluoropentylsulfinyl, 6-fluorohexylsulfinyl,6-chlorohexylsulfinyl, 6-bromohexylsulfinyl, 6-iodohexylsulfinyl ordodecafluorohexylsulfinyl.

“C₁-C₂-Alkylsulfonyl” is a C₁-C₂-alkyl group, as defined above, attachedvia a sulfonyl [S(O)₂] group to the remainder of the molecule.“C₁-C₃-Alkylsulfonyl” is a C₁-C₃-alkyl group, as defined above, attachedvia a sulfonyl [S(O)₂] group to the remainder of the molecule.“C₁-C₄-Alkylsulfonyl” is a C₁-C₄-alkyl group, as defined above, attachedvia a sulfonyl [S(O)₂] group to the remainder of the molecule.“C₁-C₆-Alkylsulfonyl” is a C₁-C₆-alkyl group, as defined above, attachedvia a sulfonyl [S(O)₂] group to the remainder of the molecule.C₁-C₂-Alkylsulfonyl is methylsulfonyl or ethylsulfonyl. Examples forC₁-C₃-alkylsulfonyl are, in addition to those mentioned forC₁-C₂-alkylsulfonyl, n-propylsulfonyl or 1-methylethylsulfonyl(isopropylsulfonyl). Examples for C₁-C₄-alkylsulfonyl are, in additionto those mentioned for C₁-C₃-alkylsulfonyl, butylsulfonyl,1-methylpropylsulfonyl (sec-butylsulfonyl), 2-methylpropylsulfonyl(isobutylsulfonyl) or 1,1-dimethylethylsulfonyl (tert-butylsulfonyl).Examples for C₁-C₆-alkylsulfonyl are, in addition to those mentioned forC₁-C₄-alkylsulfonyl, pentylsulfonyl, 1-methylbutylsulfonyl,2-methylbutylsulfonyl, 3-methylbutylsulfonyl,1,1-dimethylpropylsulfonyl, 1,2-dimethylpropylsulfonyl,2,2-dimethylpropylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl,1-methylpentylsulfonyl, 2-methylpentylsulfonyl, 3-methylpentylsulfonyl,4-methylpentylsulfonyl, 1,1-dimethylbutylsulfonyl,1,2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl,2,2-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl,3,3-dimethylbutylsulfonyl, 1-ethylbutylsulfonyl, 2-ethylbutylsulfonyl,1,1,2-trimethylpropylsulfonyl, 1,2,2-trimethylpropylsulfonyl,1-ethyl-1-methylpropylsulfonyl or 1-ethyl-2-methylpropylsulfonyl.

“C₁-C₂-Haloalkylsulfonyl” is a C₁-C₂-haloalkyl group, as defined above,attached via a sulfonyl [S(O)₂] group to the remainder of the molecule.“C₁-C₃-Haloalkylsulfonyl” is a C₁-C₃-haloalkyl group, as defined above,attached via a sulfonyl [S(O)₂] group to the remainder of the molecule.“C₁-C₄-Haloalkylsulfonyl” is a C₁-C₄-haloalkyl group, as defined above,attached via a sulfonyl [S(O)₂] group to the remainder of the molecule.“C₁-C₆-Haloalkylsulfonyl” is a C₁-C₆-haloalkyl group, as defined above,attached via a sulfonyl [S(O)₂] group to the remainder of the molecule.C₁-C₂-Haloalkylsulfonyl is, for example, S(O)₂CH₂F, S(O)₂CHF₂, S(O)₂CF₃,S(O)₂CH₂Cl, S(O)₂CHCl₂, S(O)₂CCl₃, chlorofluoromethylsulfonyl,dichlorofluoromethylsulfonyl, chlorodifluoromethylsulfonyl,2-fluoroethylsulfonyl, 2-chloroethylsulfonyl, 2-bromoethylsulfonyl,2-iodoethylsulfonyl, 2,2-difluoroethylsulfonyl,2,2,2-trifluoroethylsulfonyl, 2-chloro-2-fluoroethylsulfonyl,2-chloro-2,2-difluoroethylsulfonyl, 2,2-dichloro-2-fluoroethylsulfonyl,2,2,2-trichloroethylsulfonyl or S(O)₂C2F₅. Examples forC₁-C₃-haloalkylsulfonyl are, in addition to those mentioned forC₁-C₂-haloalkylsulfonyl, 2-fluoropropylsulfonyl, 3-fluoropropylsulfonyl,2,2-difluoropropylsulfonyl, 2,3-difluoropropylsulfonyl,2-chloropropylsulfonyl, 3-chloropropylsulfonyl,2,3-dichloropropylsulfonyl, 2-bromopropylsulfonyl,3-bromopropylsulfonyl, 3,3,3-trifluoropropylsulfonyl,3,3,3-trichloropropylsulfonyl, S(O)₂CH₂—C₂Fs, S(O)₂CF₂—C₂Fs,1-(CH₂F)-2-fluoroethylsulfonyl, 1-(CH₂Cl)-2-chloroethylsulfonylor1-(CH₂Br)-2-bromoethylsulfonyl. Examples for C₁-C₄-haloalkylsulfonylare, in addition to those mentioned for C₁-C₃-haloalkylsulfonyl,4-fluorobutylsulfonyl, 4-chlorobutylsulfonyl, 4-bromobutylsulfonyl ornonafluorobutylsulfonyl. Examples for C₁-C₆-haloalkylsulfonyl are, inaddition to those mentioned for C₁-C₄-haloalkylsulfonyl,5-fluoropentylsulfonyl, 5-chloropentylsulfonyl, 5-brompentylsulfonyl,5-iodopentylsulfonyl, undecafluoropentylsulfonyl, 6-fluorohexylsulfonyl,6-chlorohexylsulfonyl, 6-bromohexylsulfonyl, 6-iodohexylsulfonyl ordodecafluorohexylsulfonyl.

“Formyl” is a group —CH(═O).

“C₁-C₆-Alkylcarbonyl” is a C₁-C₆-alkyl group, as defined above, attachedvia a carbonyl [C(═O)] group to the remainder of the molecule.“C₁-C₄-Alkylcarbonyl” is a C₁-C₄-alkyl group, as defined above, attachedvia a carbonyl [C(═O)] group to the remainder of the molecule Examplesare acetyl (methylcarbonyl), propionyl (ethylcarbonyl), propylcarbonyl,isopropylcarbonyl, n-butylcarbonyl and the like.

“C₁-C₆-Haloalkylcarbonyl” is a C₁-C₆-haloalkyl group, as defined above,attached via a carbonyl [C(═O)] group to the remainder of the molecule.“C₁-C₄-Haloalkylcarbonyl” is a C₁-C₄-haloalkyl group, as defined above,attached via a carbonyl [C(═O)] group to the remainder of the molecule.Examples are trifluoromethylcarbonyl, 2,2,2-trifluoroethylcarbonyl andthe like.

“Carboxyl” is a group —C(═O)OH.

“Carboxyl-C₁-C₂-alkyl” is a carboxyl group bound via a C₁-C₂-alkylgroup, i.e. —CH₂—C(O)OH, —CH₂CH₂—C(O)OH or CH(CH₃)—C(O)OH.

“C₁-C₆-Alkoxycarbonyl” is a C₁-C₆-alkoxy group, as defined above,attached via a carbonyl [C(═O)] group to the remainder of the molecule.“C₁-C₄-Alkoxycarbonyl” is a C₁-C₄-alkoxy group, as defined above,attached via a carbonyl [C(═O)] group to the remainder of the molecule.Examples are methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, n-butoxycarbonyl and the like.

“C₁-C₆-Haloalkoxycarbonyl” is a C₁-C₆-haloalkoxy group, as definedabove, attached via a carbonyl [C(═O)] group to the remainder of themolecule. “C₁-C₄-Haloalkoxycarbonyl” is a C₁-C₄-haloalkoxy group, asdefined above, attached via a carbonyl [C(═O)] group to the remainder ofthe molecule. Examples are trifluoromethoxycarbonyl,2,2,2-trifluoroethoxycarbonyl and the like.

“Amino” is —NH₂.

“C₁-C₆-alkylamino” is a group —N(H)—C₁-C₆-alkyl, where C₁-C₆-alkyl is asdefined above Examples are methylamino, ethylamino, propylamino,isopropylamino, butylamino and the like.

The term “di(C₁-C₆-alkyl)amino” is a group —N(C₁-C₆-alkyl)₂, where eachC₁-C₆-alkyl is independently as defined above. Examples aredimethylamino, diethylamino, ethylmethylamino, dipropylamino,diisopropylamino, methylpropylamino, methylisopropylamino,ethylpropylamino, ethylisopropylamino, dibutylamino and the like.

“Aminocarbonyl” is —C(O)—NH₂.

The term “C₁-C₆-alkylaminocarbonyl” is a group —C(═O)—N(H)—C₁-C₆-alkyl,where C₁-C₆-alkyl is as defined above Examples are methylaminocarbonyl,ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl,butylaminocarbonyl and the like.

The term “di(C₁-C₆-alkyl)aminocarbonyl” is a group—C(═O)—N(C₁-C₆-alkyl)₂, where each C₁-C₆-alkyl is independently asdefined above. Examples are dimethylaminocarbonyl, diethylaminocarbonyl,ethylmethylaminocarbonyl, dipropylaminocarbonyl,diisopropylaminocarbonyl, methylpropylaminocarbonyl,methylisopropylaminocarbonyl, ethylpropylaminocarbonyl,ethylisopropylaminocarbonyl, dibutylaminocarbonyl and the like.

The substituent “oxo” replaces a CH₂ group by a C(═O) group.

“Ethyndiyl” is —C≡C—.

N-bound saturated 4-, 5- or 6-membered heteromonocyclic rings containingone nitrogen atom as ring member are azetidin-1-yl, pyrrolidin-1-yl orpiperidine-1-yl.

N-bound saturated 3-, 4-, 5-, 6-, 7- or 8-membered heteromonocyclicrings containing one nitrogen atom as ring member are aziridin-1-yl,azetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl, azepan-1-yl orazocan-1-yl.

Examples for N-bound saturated 4-, 5- or 6-membered heteromonocyclicrings containing 1 or 2 nitrogen atoms as ring members areazetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl, pyrazolidin-1-yl,imidazolodin-1-yl, piperazin-1-yl, hexahydropyridazin-1-yl orhexahydropyrimidin-1-yl.

Examples for N-bound saturated 3-, 4-, 5-, 6-, 7- or 8-memberedheteromonocyclic rings containing 1 or 2 nitrogen atoms as ring memberare aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl,azepan-1-yl, azocan-1-yl, pyrazolidin-1-yl, imidazolodin-1-yl,piperazin-1-yl, hexahydropyridazin-1-yl, hexahydropyrimidin-1-yl,1,2-diazepan-1-yl, 1,3-diazepan-1-yl, 1,4-diazepan-1-yl,1,2-diazocan-1-yl, 1,3-diazocan-1-yl and 1,4-diazocan-1-yl.

The term “N-bound saturated 7-, 8-, 9-, 10-, 11- or 12-memberedheterobicyclic rings containing one nitrogen atom as ring member”comprises condensed (fused) ring systems, in which the two rings havetwo neighboring ring atoms in common, as well as bridged systems with atleast three ring atoms in common.

Examples for fused systems of N-bound saturated 7-, 8-, 9-, 10-, 11- or12-membered heterobicyclic rings containing one nitrogen atom as ringmember are following structures:

Examples for fused N-bound saturated 7-, 8-, 9-, 10-, 11- or 12-memberedheterobicyclic rings containing one or two nitrogen atoms as ringmembers are the above structures of fused N-bound saturated 7-, 8-, 9-,10-, 11- or 12-membered heterobicyclic rings containing one nitrogenatom as ring member, and additionally following structures:

Examples for bridged systems of N-bound saturated 7-, 8-, 9-, 10-, 11-or 12-membered heterobicyclic rings containing one nitrogen atom as ringmember are following structures:

Examples for bridged systems of N-bound saturated 7-, 8-, 9-, 10-, 11-or 12-membered heterobicyclic rings containing one or two nitrogen atomsas ring members are the above structures of bridged N-bound saturated7-, 8-, 9-, 10-, 11- or 12-membered heterobicyclic rings containing onenitrogen atom as ring member, and additionally following structures:

In the above structures, # denotes the attachment point to the remainderof the molecule. If the rings carry one or more substituents, these maybe bound to a carbon or a nitrogen ring atom and to any one of the tworings.

The term “3-, 4-, 5-, 6-, 7- or 8-membered saturated, partiallyunsaturated or maximally unsaturated heterocyclic ring containing 1, 2or 3 heteroatoms or heteroatom groups selected from the group consistingof N, O, S, NO, SO and SO₂, as ring members” [wherein “maximumunsaturated” includes also “aromatic” ] as used herein denotesmonocyclic radicals, the monocyclic radicals being saturated, partiallyunsaturated or maximum unsaturated (including aromatic).

Unsaturated rings contain at least one C—C and/or C—N and/or N—N doublebond(s). Maximally unsaturated rings contain as many conjugated C—Cand/or C—N and/or N—N double bonds as allowed by the ring size.Maximally unsaturated 5- or 6-membered heteromonocyclic rings aregenerally aromatic (and thus not enclosed in the present term“heterocyclic ring” or “heterocyclyl”. Exceptions are maximallyunsaturated 6-membered rings containing O, S, SO and/or SO₂ as ringmembers, such as pyran and thiopyran, which are not aromatic). Partiallyunsaturated rings contain less than the maximum number of C—C and/or C—Nand/or N—N double bond(s) allowed by the ring size. The heterocyclicring may be attached to the remainder of the molecule via a carbon ringmember or via a nitrogen ring member. As a matter of course, theheterocyclic ring contains at least one carbon ring atom. If the ringcontains more than one O ring atom, these are not adjacent.

Examples of a 3-, 4-, 5-, 6-, 7- or 8-membered saturatedheteromonocyclic ring include: Oxiran-2-yl, thiiran-2-yl, aziridin-1-yl,aziridin-2-yl, oxetan-2-yl, oxetan-3-yl, thietan-2-yl, thietan-3-yl,1-oxothietan-2-yl, 1-oxothietan-3-yl, 1,1-dioxothietan-2-yl,1,1-dioxothietan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl,tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl,tetrahydrothien-3-yl, 1-oxotetrahydrothien-2-yl,1,1-dioxotetrahydrothien-2-yl, 1-oxotetrahydrothien-3-yl,1,1-dioxotetrahydrothien-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl,pyrrolidin-3-yl, pyrazolidin-1-yl, pyrazolidin-3-yl, pyrazolidin-4-yl,pyrazolidin-5-yl, imidazolidin-1-yl, imidazolidin-2-yl,imidazolidin-4-yl, oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl,oxazolidin-5-yl, isoxazolidin-2-yl, isoxazolidin-3-yl,isoxazolidin-4-yl, isoxazolidin-5-yl, thiazolidin-2-yl,thiazolidin-3-yl, thiazolidin-4-yl, thiazolidin-5-yl,isothiazolidin-2-yl, isothiazolidin-3-yl, isothiazolidin-4-yl,isothiazolidin-5-yl, 1,2,4-oxadiazolidin-2-yl, 1,2,4-oxadiazolidin-3-yl,1,2,4-oxadiazolidin-4-yl, 1,2,4-oxadiazolidin-5-yl,1,2,4-thiadiazolidin-2-yl, 1,2,4-thiadiazolidin-3-yl,1,2,4-thiadiazolidin-4-yl, 1,2,4-thiadiazolidin-5-yl,1,2,4-triazolidin-1-yl, 1,2,4-triazolidin-3-yl, 1,2,4-triazolidin-4-yl,1,3,4-oxadiazolidin-2-yl, 1,3,4-oxadiazolidin-3-yl,1,3,4-thiadiazolidin-2-yl, 1,3,4-thiadiazolidin-3-yl,1,3,4-triazolidin-1-yl, 1,3,4-triazolidin-2-yl, 1,3,4-triazolidin-3-yl,tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl,1,3-dioxan-2-yl, 1,3-dioxan-4-yl, 1,3-dioxan-5-yl, 1,4-dioxan-2-yl,piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl,hexahydropyridazin-1-yl, hexahydropyridazin-3-yl,hexahydropyridazin-4-yl, hexahydropyrimidin-1-yl,hexahydropyrimidin-2-yl, hexahydropyrimidin-4-yl,hexahydropyrimidin-5-yl, piperazin-1-yl, piperazin-2-yl,1,3,5-hexahydrotriazin-1l-yl, 1,3,5-hexahydrotriazin-2-yl,1,2,4-hexahydrotriazin-1-yl, 1,2,4-hexahydrotriazin-2-yl,1,2,4-hexahydrotriazin-3-yl, 1,2,4-hexahydrotriazin-4-yl,1,2,4-hexahydrotriazin-5-yl, 1,2,4-hexahydrotriazin-6-yl,morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, thiomorpholin-2-yl,thiomorpholin-3-yl, thiomorpholin-4-yl, 1-oxothiomorpholin-2-yl,1-oxothiomorpholin-3-yl, 1-oxothiomorpholin-4-yl,1,1-dioxothiomorpholin-2-yl, 1,1-dioxothiomorpholin-3-yl,1,1-dioxothiomorpholin-4-yl, azepan-1-, -2-, -3- or -4-yl, oxepan-2-,-3-, -4- or -5-yl, hexahydro-1,3-diazepinyl, hexahydro-1,4-diazepinyl,hexahydro-1,3-oxazepinyl, hexahydro-1,4-oxazepinyl,hexahydro-1,3-dioxepinyl, hexahydro-1,4-dioxepinyl,

oxocane, thiocane, azocanyl, [1,3]diazocanyl, [1,4]diazocanyl,[1,5]diazocanyl, [1,5]oxazocanyl and the like.

Examples of a 3-, 4-, 5-, 6-, 7- or 8-membered partially unsaturatedheteromonocyclic ring include: 2,3-dihydrofuran-2-yl,2,3-dihydrofuran-3-yl, 2,4-dihydrofuran-2-yl, 2,4-dihydrofuran-3-yl,2,3-dihydrothien-2-yl, 2,3-dihydrothien-3-yl, 2,4-dihydrothien-2-yl,2,4-dihydrothien-3-yl, 2-pyrrolin-2-yl, 2-pyrrolin-3-yl,3-pyrrolin-2-yl, 3-pyrrolin-3-yl, 2-isoxazolin-3-yl, 3-isoxazolin-3-yl,4-isoxazolin-3-yl, 2-isoxazolin-4-yl, 3-isoxazolin-4-yl,4-isoxazolin-4-yl, 2-isoxazolin-5-yl, 3-isoxazolin-5-yl,4-isoxazolin-5-yl, 2-isothiazolin-3-yl, 3-isothiazolin-3-yl,4-isothiazolin-3-yl, 2-isothiazolin-4-yl, 3-isothiazolin-4-yl,4-isothiazolin-4-yl, 2-isothiazolin-5-yl, 3-isothiazolin-5-yl,4-isothiazolin-5-yl, 2,3-dihydropyrazol-1-yl, 2,3-dihydropyrazol-2-yl,2,3-dihydropyrazol-3-yl, 2,3-dihydropyrazol-4-yl,2,3-dihydropyrazol-5-yl, 3,4-dihydropyrazol-1-yl,3,4-dihydropyrazol-3-yl, 3,4-dihydropyrazol-4-yl,3,4-dihydropyrazol-5-yl, 4,5-dihydropyrazol-1-yl,4,5-dihydropyrazol-3-yl, 4,5-dihydropyrazol-4-yl,4,5-dihydropyrazol-5-yl, 2,3-dihydrooxazol-2-yl, 2,3-dihydrooxazol-3-yl,2,3-dihydrooxazol-4-yl, 2,3-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl,3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 3,4-dihydrooxazol-5-yl,3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl,2-, 3-, 4-, 5- or 6-di- or tetrahydropyridinyl, 3-di- ortetrahydropyridazinyl, 4-di- or tetrahydropyridazinyl, 2-di- ortetrahydropyrimidinyl, 4-di- or tetrahydropyrimidinyl, 5-di- ortetrahydropyrimidinyl, di- or tetrahydropyrazinyl, 1,3,5-di- ortetrahydrotriazin-2-yl, 1,2,4-di- or tetrahydrotriazin-3-yl,2,3,4,5-tetrahydro[1H]azepin-1-, -2-, -3-, -4-, -5-, -6- or -7-yl,3,4,5,6-tetrahydro[2H]azepin-2-, -3-, -4-, -5-, -6- or -7-yl,2,3,4,7-tetrahydro[1H]azepin-1-, -2-, -3-, -4-, -5-, -6- or -7-yl,2,3,6,7-tetrahydro[1H]azepin-1-, -2-, -3-, -4-, -5-, -6- or -7-yl,tetrahydrooxepinyl, such as 2,3,4,5-tetrahydro[1H]oxepin-2-, -3-, -4-,-5-, -6- or -7-yl, 2,3,4,7-tetrahydro[1H]oxepin-2-, -3-, -4-, -5-, -6-or -7-yl, 2,3,6,7-tetrahydro[1H]oxepin-2-, -3-, -4-, -5-, -6- or -7-yl,tetrahydro-1,3-diazepinyl, tetrahydro-1,4-diazepinyl,tetrahydro-1,3-oxazepinyl, tetrahydro-1,4-oxazepinyl,tetrahydro-1,3-dioxepinyl, tetrahydro-1,4-dioxepinyl,1,2,3,4,5,6-hexahydroazocine, 2,3,4,5,6,7-hexahydroazocine,1,2,3,4,5,8-hexahydroazocine, 1,2,3,4,7,8-hexahydroazocine,1,2,3,4,5,6-hexahydro-[1,5]diazocine,1,2,3,4,7,8-hexahydro-[1,5]diazocineand the like.

Examples of a 3-, 4-, 5-, 6-, 7- or 8-membered maximally unsaturated(including aromatic) heteromonocyclic ring are 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl,3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl,1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl,1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl,1,2,5-oxadiazol-3-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl,1,3,4-oxadiazol-2-yl, 1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl,1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl,4-pyridinyl, 1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl,3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl,1,2,4-triazin-5-yl, 1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl,1,2,3,4-tetrazin-5-yl, pyran-2-yl, pyran-3-yl, pyran-4-yl,thiopyran-2-yl, thiopryran-3-yl, thiopryran-4-yl, 1-oxothiopryran-2-yl,1-oxothiopryran-3-yl, 1-oxothiopryran-4-yl, 1,1-dioxothiopryran-2-yl,1,1-dioxothiopryran-3-yl, 1,1-dioxothiopryran-4-yl, 2H-oxazin-2-yl,2H-oxazin-3-yl, 2H-oxazin-4-yl, 2H-oxazin-5-yl, 2H-oxazin-6-yl,4H-oxazin-3-yl, 4H-oxazin-4-yl, 4H-oxazin-5-yl, 4H-oxazin-6-yl,6H-oxazin-3-yl, 6H-oxazin-4-yl, 7H-oxazin-5-yl, 8H-oxazin-6-yl,2H-1,3-oxazin-2-yl, 2H-1,3-oxazin-4-yl, 2H-1,3-oxazin-5-yl,2H-1,3-oxazin-6-yl, 4H-1,3-oxazin-2-yl, 4H-1,3-oxazin-4-yl,4H-1,3-oxazin-5-yl, 4H-1,3-oxazin-6-yl, 6H-1,3-oxazin-2-yl,6H-1,3-oxazin-4-yl, 6H-1,3-oxazin-5-yl, 6H-1,3-oxazin-6-yl,2H-1,4-oxazin-2-yl, 2H-1,4-oxazin-3-yl, 2H-1,4-oxazin-5-yl,2H-1,4-oxazin-6-yl, 4H-1,4-oxazin-2-yl, 4H-1,4-oxazin-3-yl,4H-1,4-oxazin-4-yl, 4H-1,4-oxazin-5-yl, 4H-1,4-oxazin-6-yl,6H-1,4-oxazin-2-yl, 6H-1,4-oxazin-3-yl, 6H-1,4-oxazin-5-yl,6H-1,4-oxazin-6-yl, 1,4-dioxine-2-yl, 1,4-oxathiin-2-yl, 1H-azepine,1H-[1,3]-diazepine, 1H-[1,4]-diazepine, [1,3]diazocine, [1,5]diazocine,[1,5]diazocine and the like.

Examples for 5- or 6-membered monocyclic heteroaromatic rings containing1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O andS as ring members are 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl,4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-triazol-1-yl,1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl, 1,2,3-triazol-1-yl,1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,5-oxadiazol-3-yl,1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl,1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl,1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl,1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl, 3-pyridazinyl,4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl,1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl,1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl, 1,2,3,4-tetrazin-5-yl andthe like.

Examples for 9- or 10-membered bicyclic heteroaromatic rings containing1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O andS as ring members are the following structures:

In the above structures, # denotes the attachment point to the remainderof the molecule. The attachment point may be at either one of the twofused rings and may be on a carbon or a nitrogen ring atom. If the ringscarry one or more substituents, these may be bound to a carbon or anitrogen ring atom and to any one of the two rings.

If R⁸ and R⁹, together with the nitrogen atom they are bound to, form a3-, 4-, 5-, 6-7- or 8-meinbered saturated heterocyclic ring which maycontain 1, 2 or 3 additional heteroatoms or heteroatom groups selectedfrom the group consisting of N, O, S, NO, S(O) and S(O)₂, this is forexample aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, pyrazolidin-1-yl,imidazolodin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl,1-oxothiazolidin-3-yl, 1,1-dioxothiazolidin-3-yl, isothiazolidin-2-yl,1-oxoisothiazolidin-2-yl, 1,1-dioxoisothiazolidin-3-yl, piperidine-1-yl,piperazin-1-yl, hexahydropyridazin-1-yl, hexahydropyrimidin-1-yl,morpholin-4-yl (morpholino), thiomorpholin-4-yl,1-oxothiomorpholin-4-yl, 1,1-diooxothiomorpholin-4-yl, azepan-1-yl,1,2-diazepan-1-yl, 1,3-diazepan-1-yl, 1,4-diazepan-1-yl, azocan-1-yl,1,2-diazocan-1-yl, 1,3-diazocan-1-yl, 1,4-diazocan-1-yl and the like.

The remarks made above and in the following with respect to preferredaspects of the invention, e.g. to preferred meanings of the variables L,R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(a), R^(b) and m of compounds I,to preferred compounds I and to preferred embodiments of the methods orthe use according to the invention, apply in each case on their own orin particular to combinations thereof.

In one embodiment of the invention (embodiment 1), R¹ is R^(a).

In an alternative embodiment of the invention (embodiment 2), R¹ isselected from the group consisting of halogen, C₁-C₂-haloalkyl,C₁-C₂-alkoxy, C₁-C₂-haloalkoxy, an N-bound saturated 3-, 4-, 5-, 6-, 7-or 8-membered heteromonocyclic ring containing one or two nitrogen atomsas ring members; and an N-bound saturated 7-, 8-, 9-, 10-, 11- or12-membered heterobicyclic ring containing one or two nitrogen atoms asring members; where the heteromonocyclic ring and the heterobicyclicring may carry one or more substituents R⁴. Simultaneously the phenyl,naphthyl, monocyclic or bicyclic heteroaromatic ring R² carries onesubstituent R^(a) and optionally also one or more substituents R⁵, whereR^(a), R⁴ and R⁵ have one of the above general or, in particular, one ofthe below preferred meanings.

In a particular embodiment of embodiment 2 (embodiment 2.1), R¹ ishalogen, and is specifically a fluorine atom (embodiment 2.1.1); andsimultaneously the phenyl, naphthyl, monocyclic or bicyclicheteroaromatic ring R² carries one substituent R^(a) and optionally alsoone or more substituents R⁵, where R^(a) and R⁵ have one of the abovegeneral or, in particular, one of the below preferred meanings.

In an alternative particular embodiment of embodiment 2 (embodiment2.2), R¹ is an N-bound saturated 3-, 4-, 5-, 6-, 7- or 8-memberedheteromonocyclic ring containing one or two nitrogen atoms as ringmembers; or an N-bound saturated 7-, 8-, 9-, 10-, 11- or 12-memberedheterobicyclic ring containing one or two nitrogen atoms as ringmembers; where the heteromonocyclic ring and the heterobicyclic ring maycarry one or more substituents R⁴; and simultaneously the phenyl,naphthyl, monocyclic or bicyclic heteroaromatic ring R² carries onesubstituent R^(a) and optionally also one or more substituents R⁵, whereR^(a), R⁴ and R⁵ have one of the above general or, in particular, one ofthe below preferred meanings.

In a specific embodiment of embodiment 2.2 (embodiment 2.2.1), R¹ is anN-bound saturated 7-, 8-, 9-, 10- or 11-membered heterobicyclic ringcontaining one or two nitrogen atoms as ring members; where theheterobicyclic ring may carry one or more substituents R⁴; andsimultaneously the phenyl, naphthyl, monocyclic or bicyclicheteroaromatic ring R² carries one substituent R^(a) and optionally alsoone or more substituents R⁵, where R^(a), R⁴ and R⁵ have one of theabove general or, in particular, one of the below preferred meanings.

In particular (embodiment 3), R^(a) is an N-bound saturated 3-, 4-, 5-,6-, 7- or 8-membered heteromonocyclic ring containing one nitrogen atomas ring member, where the heteromonocyclic ring carries 1, 2 or 3substituents R^(b) and optionally 1 or 2 further substituents R⁴, whereR^(b) and R⁴ have one of the above general or, in particular, one of thebelow preferred meanings. More particularly (embodiment 3.1), R^(a) isan N-bound saturated 3-, 4-, 5-, 6-, 7- or 8-membered heteromonocyclicring containing one nitrogen atom as ring member, where theheteromonocyclic ring carries 1, 2 or 3 substituents R^(b) andoptionally 1 or 2 further substituents R⁴, where R^(b) and R⁴ have oneof the above general or, in particular, one of the below preferredmeanings, and R¹ is as defined in any of embodiments 1, 2, 2.1, 2.1.1,2.2 or 2.2.1.

Specifically (embodiment 3.2), R^(a) is an N-bound saturated 4-, 5- or6-membered heteromonocyclic ring containing one nitrogen atom as ringmember, where the heteromonocyclic ring carries 1 or 2 substituentsR^(b) and optionally one further substituent R⁴, where R^(b) and R⁴ haveone of the above general or, in particular, one of the below preferredmeanings. More specifically (embodiment 3.2.1), R^(a) is an N-boundsaturated 4-, 5- or 6-membered heteromonocyclic ring containing onenitrogen atom as ring member, where the heteromonocyclic ring carries 1or 2 substituents R^(b) and optionally one further substituent R⁴, whereR^(b) and R⁴ have one of the above general or, in particular, one of thebelow preferred meanings, and R¹ is as defined in any of embodiments 1,2, 2.1, 2.1.1, 2.2 or 2.2.1.

In another particular embodiment (embodiment 4), R^(a) is an N-boundsaturated 7-, 8-, 9-, 10-, 11- or 12-membered heterobicyclic ringcontaining one nitrogen atom as ring member, where the heterobicyclicring carries 1, 2 or 3 substituents R^(b) and optionally 1 or 2 furthersubstituents R⁴, where R^(b) and R⁴ have one of the above general or, inparticular, one of the below preferred meanings. More particularly(embodiment 4.1), R^(a) is an N-bound saturated 7-, 8-, 9-, 10-, 11- or12-membered heterobicyclic ring containing one nitrogen atom as ringmember, where the heterobicyclic ring carries 1, 2 or 3 substituentsR^(b) and optionally 1 or 2 further substituents R⁴, where R^(b) and R⁴have one of the above general or, in particular, one of the belowpreferred meanings, and R¹ is as defined in any of embodiments 1, 2,2.1, 2.1.1, 2.2 or 2.2.1.

Specifically (embodiment 4.2), R^(a) is an N-bound saturated 7-, 8-, 9-or 10-membered heterobicyclic ring containing one nitrogen atom as ringmember, where the heterobicyclic ring carries 1 or 2 substituents R^(b)and optionally one further substituent R⁴, where R^(b) and R⁴ have oneof the above general or, in particular, one of the below preferredmeanings. More specifically (embodiment 4.2.1), R^(a) is an N-boundsaturated 7-, 8-, 9- or 10-membered heterobicyclic ring containing onenitrogen atom as ring member, where the heterobicyclic ring carries 1 or2 substituents R^(b) and optionally one further substituent R⁴, whereR^(b) and R⁴ have one of the above general or, in particular, one of thebelow preferred meanings, and R¹ is as defined in any of embodiments 1,2, 2.1, 2.1.1, 2.2 or 2.2.1.

In a preferred embodiment (embodiment 5), the oxygen-containing radicalR^(b) is selected from the group consisting of hydroxyl (—OH), carboxyl(—C(O)OH), —CH₂—C(O)OH and —C(O)NH₂. In particular (embodiment 5.1), theoxygen-containing radical R^(b) is selected from the group consisting ofhydroxyl, —C(O)OH, —CH₂—C(O)OH and —C(O)NH₂, and R¹ and R^(a) are asdefined in any of embodiments 1, 2, 2.1, 2.1.1, 2.2, 2.2.1, 3, 3.1, 3.2,3.2.1, 4, 4.1, 4.2 or 4.2.1.

Specifically (embodiment 5.2), the oxygen-containing radical R^(b) isselected from the group consisting of hydroxyl, carboxyl and —C(O)NH₂.More specifically (embodiment 5.2.1), the oxygen-containing radicalR^(b) is selected from the group consisting of hydroxyl and carboxyl,and R¹ and R^(a) are as defined in any of embodiments 1, 2, 2.1, 2.1.1,2.2, 2.2.1, 3, 3.1, 3.2, 3.2.1, 4, 4.1, 4.2 or 4.2.1.

Even more specifically, (embodiment 5.3), the oxygen-containing radicalR^(b) is selected from the group consisting of hydroxyl and carboxyl.Very specifically (embodiment 5.3.1), the oxygen-containing radicalR^(b) is selected from the group consisting of hydroxyl and carboxyl,and R¹ and R^(a) are as defined in any of embodiments 1, 2, 2.1, 2.1.1,2.2, 2.2.1, 3, 3.1, 3.2, 3.2.1, 4, 4.1, 4.2 or 4.2.1.

In a preferred embodiment of embodiments 5.2, 5.2.1, 5.3 and 5.3.1,(embodiment 5.4), if R^(b) is OH, R^(a) carries 1 or 2 OH groups (and noother substituent R^(b)); if R^(b) is COOH or —C(O)NH₂, R^(a) carriesone COOH group or one —C(O)NH₂ group (and no other substituent R^(b)),and if R^(b) is —CH₂—C(O)OH, R^(a) carries one —CH₂—C(O)OH group (and noother substituent R^(b)).

In a preferred embodiment (embodiment 6), each R⁴ is independentlyselected from the group consisting of halogen, C₁-C₄-alkyl andC₁-C₄-haloalkyl. In particular (embodiment 6.1), each R⁴ isindependently selected from the group consisting of halogen, C₁-C₄-alkyland C₁-C₄-haloalkyl, and R¹, R^(a) and R^(b) are as defined in any ofembodiments 1, 2, 2.1, 2.1.1, 2.2, 2.2.1, 3, 3.1, 3.2, 3.2.1, 4, 4.1,4.2, 4.2.1, 5, 5.1, 5.2, 5.2.1, 5.3, 5.3.1 or 5.4. Specifically,(embodiment 6.2), each R⁴ is independently selected from the groupconsisting of halogen and C₁-C₄-alkyl. More specifically, (embodiment6.2.1), each R⁴ is independently selected from the group consisting ofhalogen and C₁-C₄-alkyl, and R¹, R^(a) and R^(b) are as defined in anyof embodiments 1, 2, 2.1, 2.1.1, 2.2, 2.2.1, 3, 3.1, 3.2, 3.2.1, 4, 4.1,4.2, 4.2.1, 5, 5.1, 5.2, 5.2.1, 5.3, 5.3.1 or 5.4. Even morespecifically, (embodiment 6.2.1.1), each R⁴ is independently F ormethyl, and R¹, R^(a) and R^(b) are as defined in any of embodiments 1,2, 2.1, 2.1.1, 2.2, 2.2.1, 3, 3.1, 3.2, 3.2.1, 4, 4.1, 4.2, 4.2.1, 5,5.1, 5.2, 5.2.1, 5.3, 5.3.1 or 5.4.

In a preferred embodiment (embodiment 7), L is S(O)₂. In particular(embodiment 7.1), L is S(O)₂, and R¹, R^(a), R^(b) and R⁴ are as definedin any of embodiments 1, 2, 2.1, 2.1.1, 2.2, 2.2.1, 3, 3.1, 3.2, 3.2.1,4, 4.1, 4.2, 4.2.1, 5, 5.1, 5.2, 5.2.1, 5.3, 5.3.1, 5.4, 6, 6.1, 6.2,6.2.1 or 6.2.1.1.

In a preferred embodiment (embodiment 8), R² is phenyl which may besubstituted (or is substituted, if R¹ is not R^(a)) as defined above orbelow. In particular (embodiment 8.1), R² is phenyl which may besubstituted (or is substituted, if R¹ is not R^(a)) as defined above orbelow, and R¹, R^(a), R^(b), R⁴ and L are as defined in any ofembodiments 1, 2, 2.1, 2.1.1, 2.2, 2.2.1, 3, 3.1, 3.2, 3.2.1, 4, 4.1,4.2, 4.2.1, 5, 5.1, 5.2, 5.2.1, 5.3, 5.3.1, 5.4, 6, 6.1, 6.2, 6.2.1,6.2.1.1, 7 or 7.1.

In a preferred embodiment (embodiment 9), each R⁵ is independentlyselected from the group consisting of halogen, cyano, hydroxyl,C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, COOH,CONH₂ and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated heterocyclic ringcontaining 1, 2 or 3 heteroatoms or heteroatom groups selected from thegroup consisting of N, O, S, NO, S(O) and S(O)₂ as ring members, whereheterocyclic ring may carry one or more substituents R⁷; where each R⁷is independently selected from the group consisting of halogen,C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy and C₁-C₆-haloalkoxy. Inparticular (embodiment 9.1), each R⁵ is independently selected from thegroup consisting of halogen, cyano, hydroxyl, C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, COOH, CONH₂ and a 3-,4-, 5-, 6-, 7- or 8-membered saturated heterocyclic ring containing 1, 2or 3 heteroatoms or heteroatom groups selected from the group consistingof N, O, S, NO, S(O) and S(O)₂ as ring members, where the heterocyclicring may carry one or more substituents R⁷; where each R⁷ isindependently selected from the group consisting of halogen,C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy and C₁-C₆-haloalkoxy, and R¹,R^(a), R^(b), R⁴, L and R² are as defined in any of embodiments 1, 2,2.1, 2.1.1, 2.2, 2.2.1, 3, 3.1, 3.2, 3.2.1, 4, 4.1, 4.2, 4.2.1, 5, 5.1,5.2, 5.2.1, 5.3, 5.3.1, 5.4, 6, 6.1, 6.2, 6.2.1, 6.2.1.1, 7, 7.1, 8 or8.1. In a specific embodiment (embodiment 9.2), each R⁵ is independentlyselected from the group consisting of halogen, cyano, hydroxyl,C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, and a 3-,4-, 5-, 6-, 7- or 8-membered saturated heterocyclic ring containing 1, 2or 3 heteroatoms or heteroatom groups selected from the group consistingof N, O, S, NO, S(O) and S(O)₂ as ring members, where heterocyclic ringmay carry one or more substituents R⁷; where each R⁷ is independentlyselected from the group consisting of halogen, C₁-C₆-alkyl andC₁-C₆-haloalkyl. More specifically (embodiment 9.2.1), each R⁵ isindependently selected from the group consisting of halogen, cyano,hydroxyl, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated heterocyclic ringcontaining 1, 2 or 3 heteroatoms or heteroatom groups selected from thegroup consisting of N, O, S, NO, S(O) and S(O)₂ as ring members, wherethe heterocyclic ring may carry one or more substituents R⁷; where eachR⁷ is independently selected from the group consisting of halogen,C₁-C₆-alkyl and C₁-C₆-haloalkyl, and R¹, R^(a), R^(b), R⁴, L and R² areas defined in any of embodiments 1, 2, 2.1, 2.1.1, 2.2, 2.2.1, 3, 3.1,3.2, 3.2.1, 4, 4.1, 4.2, 4.2.1, 5, 5.1, 5.2, 5.2.1, 5.3, 5.3.1, 5.4, 6,6.1, 6.2, 6.2.1, 6.2.1.1, 7, 7.1, 8 or 8.1.

The 3-, 4-, 5-, 6-, 7- or 8-membered saturated heterocyclic ring R⁵containing 1, 2 or 3 heteroatoms or heteroatom groups selected from thegroup consisting of N, O, S, NO, S(O) and S(O)₂ as ring members ispreferably a 5- or 6-membered saturated heterocyclic ring containing 1or 2 nitrogen atoms as ring members, where the heterocyclic ring maycarry one or more substituents R⁷; where each R⁷ is independentlyselected from the group consisting of halogen, C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₁-C₆-alkoxy and C₁-C₆-haloalkoxy, and is in particularC₁-C₄-alkyl or C₁-C₄-alkoxy.

In a preferred embodiment (embodiment 10), m is 0. In particular(embodiment 10.1), m is 0 and R¹, R^(a), R^(b), R⁴, L, R² and R⁵ are asdefined in any of embodiments 1, 2, 2.1, 2.1.1, 2.2, 2.2.1, 3, 3.1, 3.2,3.2.1, 4, 4.1, 4.2, 4.2.1, 5, 5.1, 5.2, 5.2.1, 5.3, 5.3.1, 5.4, 6, 6.1,6.2, 6.2.1, 6.2.1.1, 7, 7.1, 8, 8.1, 9 or 9.1.

In particular, the compound I is a compound of formula I.1

where R¹ and R² have one of the above general or, in particular, one ofthe above preferred definitions.Specifically, in compounds I.1,

-   R¹ is R^(a), which is in turn an N-bound saturated heterocyclic ring    selected from the group consisting of azetidin-1-yl, pyrrolidin-1-yl    and piperidin-1-yl, where the ring carries one or two substituents    R^(b) which have one of the above general or, in particular, one of    the above preferred definitions and are in particular OH, COOH,    CONH₂ or —CH₂—COOH and are specifically OH, COOH or CONH₂ and are    very specifically OH or COOH, and carries optionally one or two    substituents R⁴ which have one of the above general or, in    particular, one of the above preferred definitions; and-   R² is phenyl which may be substituted by 1 or 2 substituents    selected from the group consisting of halogen, cyano, hydroxyl,    C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, COOH,    CONH₂ and an N-bound saturated heterocyclic ring selected from the    group consisting of azetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl    and piperazin-1-yl, where the ring carries one or two substituents    selected from the group consisting of C₁-C₆-alkyl, C₁-C₆-haloalkyl,    C₁-C₆-alkoxy, OH and COOH, where R² is in particular phenyl which    may be substituted by 1 or 2 substituents selected from the group    consisting of halogen, cyano, hydroxyl, C₁-C₆-alkyl,    C₁-C₆-haloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, and an N-bound    saturated heterocyclic ring selected from the group consisting of    azetidin-1-yl, pyrrolidin-1-yl and piperidine-1-yl, where the    heterocyclic ring carries one or two substituents selected from the    group consisting of C₁-C₆-alkyl, C₁-C₆-haloalkyl, OH and COOH.    More specifically, in compounds I.1,-   R¹ is R^(a), which is in turn an N-bound saturated heterocyclic ring    selected from azetidin-1-yl, pyrrolidin-1-yl and piperidine-1-yl,    where the ring carries one or two OH groups or one COOH group or one    CONH₂ group or one —CH₂—COOH group, and carries optionally one or    two substituents R⁴ selected from the group consisting of F, CH₃,    CHF₂ and CF₃; and-   R² is phenyl which may be substituted by 1 or 2 substituents    selected from the group consisting of halogen, cyano, hydroxyl,    C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy, COOH, CONH₂ and an    N-bound saturated heterocyclic ring selected from the group    consisting of azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl and    piperazin-1-yl, where the heterocyclic ring carries one or two    substituents selected from the group consisting of C₁-C₆-alkyl,    C₁-C₆-haloalkyl, C₁-C₆-alkoxy, OH and COOH and in particular    selected from the group consisting of C₁-C₆-alkyl, C₁-C₆-alkoxy, OH    and COOH.    Even more specifically, in compounds I.1,-   R¹ is R^(a), which is in turn an N-bound saturated heterocyclic ring    selected from azetidin-1-yl, pyrrolidin-1-yl and piperidine-1-yl,    where the ring carries one or two OH groups or one COOH or one CONH₂    group, and carries optionally one or two substituents R⁴ selected    from the group consisting of F, CH₃, CHF₂ and CF₃; and-   R² is phenyl which may be substituted by 1 or 2 substituents    selected from the group consisting of halogen, cyano, hydroxyl,    C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy, and an N-bound saturated    heterocyclic ring selected from the group consisting of    azetidin-1-yl, pyrrolidin-1-yl and piperidin-1-yl, where the    heterocyclic ring carries one or two substituents selected from the    group consisting of C₁-C₆-alkyl, C₁-C₆-haloalkyl, OH and COOH.    Very specifically, in compounds I.1,-   R¹ is R^(a), which is in turn an N-bound saturated heterocyclic ring    selected from azetidin-1-yl, pyrrolidin-1-yl and piperidine-1-yl,    where the ring carries one or two OH groups or one COOH group, and    carries optionally one methyl substituent; and-   R² is phenyl which may be substituted by 1 or 2 substituents    selected from the group consisting of halogen, hydroxyl,    C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy, and an N-bound saturated    heterocyclic ring selected from the group consisting of    azetidin-1-yl, pyrrolidin-1-yl and piperidin-1-yl, where the    heterocyclic ring carries one or two substituents selected from the    group consisting of OH and COOH.    In another specific embodiment, in compounds I. 1,-   R¹ is F; and-   R² is phenyl which carries one ring R^(a), which is in turn an    N-bound saturated heterocyclic ring selected from the group    consisting of azetidin-1-yl, pyrrolidin-1-yl and piperidine-1-yl,    where the heterocyclic ring carries one or two substituents R^(b)    which have one of the above general or, in particular, one of the    above preferred definitions and are in particular OH or COOH, and    carries optionally one or two substituents R⁴ which have one of the    above general or, in particular, one of the above preferred    definitions; where the phenyl ring may additionally carry 1 or 2    substituents selected from the group consisting of halogen, cyano,    hydroxyl, C₁-C₆-alkyl, C₁-C₆-haloalkyl and C₁-C₆-alkoxy.    In another more specific embodiment, in compounds I.1,-   R¹ is F; and-   R² is phenyl which carries one ring R^(a), which is in turn an    N-bound saturated heterocyclic ring selected from the group    consisting of azetidin-1-yl, pyrrolidin-1-yl and piperidine-1-yl,    where the heterocyclic ring carries one or two OH groups or one COOH    group, and carries optionally one or two substituents R⁴ selected    from the group consisting of F, CH₃, CHF₂ and CF₃.

Examples of preferred compounds are compounds of the following formulaeI.a to I.g and the stereoisomers thereof, where R¹ has one of thegeneral or preferred meanings given above, R^(5a) is R⁵ and/or R^(a) andn is 0, 1, 2, 3, 4 or 5. Examples of preferred compounds are theindividual compounds compiled in the tables 1 to 525 below. Moreover,the meanings mentioned below for the individual variables in the tablesare per se, independently of the combination in which they arementioned, a particularly preferred embodiment of the substituents inquestion.

Table 1

Compounds of the formula I.a in which R¹ is ring R^(a).1 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 2

Compounds of the formula I.a in which R¹ is ring R^(a).2 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 3

Compounds of the formula I.a in which R¹ is ring R^(a).3 and (R^(5a))for a compound corresponds in each case to one row of Table A

Table 4

Compounds of the formula I.a in which R¹ is ring R^(a).4 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 5

Compounds of the formula I.a in which R¹ is ring R^(a).5 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 6

Compounds of the formula I.a in which R¹ is ring R^(a).6 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 7

Compounds of the formula I.a in which R¹ is ring R^(a).7 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 8

Compounds of the formula I.a in which R¹ is ring R^(a).8 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 9

Compounds of the formula I.a in which R¹ is ring R^(a).9 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 10

Compounds of the formula I.a in which R¹ is ring R^(a.)10 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 11

Compounds of the formula I.a in which R¹ is ring R^(a).11 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 12

Compounds of the formula I.a in which R¹ is ring R^(a).12 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 13

Compounds of the formula I.a in which R¹ is ring R^(a).13 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 14

Compounds of the formula I.a in which R¹ is ring R^(a).14 and (R^(5a)),for a compound corresponds in each case to one row of Table A

Table 15

Compounds of the formula I.a in which R¹ is ring R^(a).15 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 16

Compounds of the formula I.a in which R¹ is ring R^(a).16 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 17

Compounds of the formula I.a in which R¹ is ring R^(a).17 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 18

Compounds of the formula I.a in which R¹ is ring R^(a).18 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 19

Compounds of the formula I.a in which R¹ is ring R^(a).19 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 20

Compounds of the formula I.a in which R¹ is ring R^(a).20 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 21

Compounds of the formula I.a in which R¹ is ring R^(a).21 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 22

Compounds of the formula I.a in which R¹ is ring R^(a).22 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 23

Compounds of the formula I.a in which R¹ is ring R^(a).23 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 24

Compounds of the formula I.a in which R¹ is ring R^(a).24 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 25

Compounds of the formula I.a in which R¹ is ring R^(a).25 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 26

Compounds of the formula I.a in which R¹ is ring R^(a).26 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 27

Compounds of the formula I.a in which R¹ is ring R^(a).27 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 28

Compounds of the formula I.a in which R¹ is ring R^(a).28 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 29

Compounds of the formula I.a in which R¹ is ring R^(a).29 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 30

Compounds of the formula I.a in which R¹ is ring R^(a).30 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 31

Compounds of the formula I.a in which R¹ is ring R^(a).31 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 32

Compounds of the formula I.a in which R¹ is ring R^(a).32 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 33

Compounds of the formula I.a in which R¹ is ring R^(a).33 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 34

Compounds of the formula I.a in which R¹ is ring R^(a).34 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 35

Compounds of the formula I.a in which R¹ is ring R^(a).35 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 36

Compounds of the formula I.a in which R¹ is ring R^(a).36 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 37

Compounds of the formula I.a in which R¹ is ring R^(a).37 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 38

Compounds of the formula I.a in which R¹ is ring R^(a).38 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 39

Compounds of the formula I.a in which R¹ is ring R^(a).39 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 40

Compounds of the formula I.a in which R¹ is ring R^(a).40 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 41

Compounds of the formula I.a in which R¹ is ring R^(a).41 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 42

Compounds of the formula I.a in which R¹ is ring R^(a).42 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 43

Compounds of the formula I.a in which R¹ is ring R^(a).43 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 44

Compounds of the formula I.a in which R¹ is ring R^(a).44 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 45

Compounds of the formula I.a in which R¹ is ring R^(a).45 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 46

Compounds of the formula I.a in which R¹ is ring R^(a).46 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 47

Compounds of the formula I.a in which R¹ is ring R^(a).47 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 48

Compounds of the formula I.a in which R¹ is ring R^(a).48 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 49

Compounds of the formula I.a in which R¹ is ring R^(a).49 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 50

Compounds of the formula I.a in which R¹ is ring R^(a).50 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 51

Compounds of the formula I.a in which R¹ is ring R^(a).51 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 52

Compounds of the formula I.a in which R¹ is ring R^(a).52 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 53

Compounds of the formula I.a in which R¹ is ring R^(a).53 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 54

Compounds of the formula I.a in which R¹ is ring R^(a).54 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 55

Compounds of the formula I.a in which R¹ is ring R^(a).55 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 56

Compounds of the formula I.a in which R¹ is ring R^(a).56 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 57

Compounds of the formula I.a in which R¹ is ring R^(a).57 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 58

Compounds of the formula I.a in which R¹ is ring R^(a).58 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 59

Compounds of the formula I.a in which R¹ is ring R^(a).59 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 60

Compounds of the formula I.a in which R¹ is ring R^(a).60 and(R^(5a))_(n) for a compound corresponds in each case to one row of TableA

Table 61

Compounds of the formula I.a in which R¹ is F and (R^(5a))_(n) for acompound corresponds in each case to one row of Table B

Table 62

Compounds of the formula I.a in which R¹ is Cl and (R^(5a))_(n) for acompound corresponds in each case to one row of Table B

Table 63

Compounds of the formula I.a in which R¹ is CHF₂ and (R^(5a))_(n) for acompound corresponds in each case to one row of Table B

Table 64

Compounds of the formula I.a in which R¹ is CF₃ and (R^(5a))_(n) for acompound corresponds in each case to one row of Table B

Table 65

Compounds of the formula I.a in which R¹ is OCF₃ and (R^(5a))_(n) for acompound corresponds in each case to one row of Table B

Table 66

Compounds of the formula I.a in which R¹ is OCHF₂ and (R^(5a))_(n) for acompound corresponds in each case to one row of Table B

Table 67

Compounds of the formula I.a in which R¹ is OCF₃ and (R^(5a))_(n) for acompound corresponds in each case to one row of Table B

Table 68

Compounds of the formula I.a in which R¹ is azetidin-1-yl and(R^(5a))_(n) for a compound corresponds in each case to one row of TableB

Table 69

Compounds of the formula I.a in which R¹ is pyrrolidin-1-yl and(R^(5a))_(n) for a compound corresponds in each case to one row of TableB

Table 70

Compounds of the formula I.a in which R¹ is piperidine-1-yl and(R^(5a))_(n) for a compound corresponds in each case to one row of TableB

Table 71

Compounds of the formula I.a in which R¹ is piperazine-1-yl and(R^(5a))_(n) for a compound corresponds in each case to one row of TableB

Table 72

Compounds of the formula I.a in which R¹ is 1-methyl-piperazine-4-yl and(R^(5a))_(n) for a compound corresponds in each case to one row of TableB

Table 73

Compounds of the formula I.a in which R¹ is octahydro-isoindol-2-yl and(R^(5a))_(n) for a compound corresponds in each case to one row of TableB

Table 74

Compounds of the formula I.a in which R¹ isoctahydro-pyrrolo[3,4-c]pyridine-2-yl and (R^(5a))_(n) for a compoundcorresponds in each case to one row of Table B

Table 75

Compounds of the formula I.a in which R¹ is5-methyl-octahydro-pyrrolo[3,4-c]pyridine-2-yl and (R^(5a))_(n) for acompound corresponds in each case to one row of Table B

Tables 76 to 150

Compounds of the formula I.b in which R¹ and (R^(5a))_(n) are as definedin any one of tables 1 to 75.

Tables 151 to 225

Compounds of the formula I.c in which R¹ and (R^(5a))_(n) are as definedin any one of tables 1 to 75.

Tables 226 to 300

Compounds of the formula I.d in which R¹ and (R^(5a))_(n) are as definedin any one of tables 1 to 75.

Tables 301 to 375

Compounds of the formula I.e in which R¹ and (R^(5a))_(n) are as definedin any one of tables 1 to 75.

Tables 376 to 450

Compounds of the formula I.f in which R¹ and (R^(5a))_(n) are as definedin any one of tables 1 to 75.

Tables 451 to 525

Compounds of the formula I.g in which R¹ and (R^(5a))_(n) are as definedin any one of tables 1 to 75.Rings R^(a).1 to R^(a).60 are depicted beneath table B. In tables A andB, the indicator (2-, 3-, 4-, 5-, 6-, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5-etc.) relates to the position to which the radical R^(5a) is bound onthe phenyl ring (for the positions see phenyl ring in the above formulaeI.a to I.i). If (R^(5a))_(n) is defined with a dash (-), this means thatn is 0 (no substituent R^(5a)).

TABLE A No. (R^(5a))_(n) A-1. — A-2. 2-F A-3. 3-F A-4. 4-F A-5. 2,3-F₂A-6. 2,4-F₂ A-7. 2,5-F₂ A-8. 2,6-F₂ A-9. 3,4-F₂ A-10. 3,5-F₂ A-11. 2-ClA-12. 3-Cl A-13. 4-Cl A-14. 2,3-Cl₂ A-15. 2,4-Cl₂ A-16. 2,5-Cl₂ A-17.2,6-Cl₂ A-18. 3,4-Cl₂ A-19. 3,5-Cl₂ A-20. 2-CN A-21. 3-CN A-22. 4-CNA-23. 2-CH₃ A-24. 3-CH₃ A-25. 4-CH₃ A-26. 2-CHF₂ A-27. 3-CHF₂ A-28.4-CHF₂ A-29. 2-CF₃ A-30. 3-CF₃ A-31. 4-CF₃ A-32. 2-OCH₃ A-33. 3-OCH₃A-34. 4-OCH₃ A-35. 2-OCHF₂ A-36. 3-OCHF₂ A-37. 4-OCHF₂ A-38. 2-OCF₃A-39. 3-OCF₃ A-40. 4-OCF₃ A-41. 2-OH, 5-CH₃ A-42. 2-OCH₃, 5-CH₃ A-43.2-COOH A-44. 3-COOH A-45. 4-COOH A-46. 2-CONH₂ A-47. 3-CONH₂ A-48.4-CONH₂ A-49. 2-(azetidin-1-yl) A-50. 3-(azetidin-1-yl) A-51.4-(azetidin-1-yl) A-52. 2-(3-hydroxyazetidin-1-yl) A-53.3-(3-hydroxyazetidin-1-yl) A-54. 4-(3-hydroxyazetidin-1-yl) A-55.2-(3-carboxyazetidin-1-yl) A-56. 3-(3-carboxyazetidin-1-yl) A-57.4-(3-carboxyazetidin-1-yl) A-58. 2-(pyrrolidin-1-yl) A-59.3-(pyrrolidin-1-yl) A-60. 4-(pyrrolidin-1-yl) A-61.2-(3-hydroxypyrrolidin-1-yl) A-62. 3-(3-hydroxypyrrolidin-1-yl) A-63.4-(3-hydroxypyrrolidin-1-yl) A-64. 2-(3-methoxypyrrolidin-1-yl) A-65.3-(3-methoxypyrrolidin-1-yl) A-66. 4-(3-methoxypyrrolidin-1-yl) A-67.2-(3-carboxypyrrolidin-1-yl) A-68. 3-(3-carboxypyrrolidin-1-yl) A-69.4-(3-carboxypyrrolidin-1-yl) A-70. 2-(piperidin-1-yl) A-71.3-(piperidin-1-yl) A-72. 4-(piperidin-1-yl) A-73.2-(4-hydroxypiperidin-1-yl) A-74. 3-(4-hydroxypiperidin-1-yl) A-75.4-(4-hydroxypiperidin-1-yl) A-76. 2-(4-carboxypiperidin-1-yl) A-77.3-(4-carboxypiperidin-1-yl) A-78. 4-(4-carboxypiperidin-1-yl) A-79.2-(piperazin-1-yl) A-80. 3-(piperazin-1-yl) A-81. 4-(piperazin-1-yl)A-82. 2-(1-methylpiperazin-4-yl) A-83. 3-(1-methylpiperazin-4-yl) A-84.4-(1-methy1piperazin-4-yl)

TABLE B No. (R^(5a))_(n) B-1 2-R^(a).1 B-2 3-R^(a).1 B-3 4-R^(a).1 B-42-R^(a).2 B-5 3-R^(a).2 B-6 4-R^(a).2 B-7 2-R^(a).3 B-8 3-R^(a).3 B-94-R^(a).3 B-10 2-R^(a).4 B-11 3-R^(a).4 B-12 4-R^(a).4 B-13 2-R^(a).5B-14 3-R^(a).5 B-15 4-R^(a).5 B-16 2-R^(a).6 B-17 3-R^(a).6 B-184-R^(a).6 B-19 2-R^(a).7 B-20 3-R^(a).7 B-21 4-R^(a).7 B-22 2-R^(a).8B-23 3-R^(a).8 B-24 4-R^(a).8 B-25 2-R^(a).9 B-26 3-R^(a).9 B-274-R^(a).9 B-28 2-R^(a).10 B-29 3-R^(a).10 B-30 4-R^(a).10 B-312-R^(a).11 B-32 3-R^(a).11 B-33 4-R^(a).11 B-34 2-R^(a).12 B-353-R^(a).12 B-36 4-R^(a).12 B-37 2-R^(a).13 B-38 3-R^(a).13 B-394-R^(a).13 B-40 2-R^(a).14 B-41 3-R^(a).14 B-42 4-R^(a).14 B-432-R^(a).15 B-44 3-R^(a).15 B-45 4-R^(a).15 B-46 2-R^(a).16 B-473-R^(a).16 B-48 4-R^(a).16 B-49 2-R^(a).17 B-50 3-R^(a).17 B-514-R^(a).17 B-52 2-R^(a).18 B-53 3-R^(a).18 B-54 4-R^(a).18 B-552-R^(a).19 B-56 3-R^(a).19 B-57 4-R^(a).19 B-58 2-R^(a).20 B-593-R^(a).20 B-60 4-R^(a).20 B-61 2-R^(a).21 B-62 3-R^(a).21 B-634-R^(a).21 B-64 2-R^(a).22 B-65 3-R^(a).22 B-66 4-R^(a).22 B-672-R^(a).23 B-68 3-R^(a).23 B-69 4-R^(a).23 B-70 2-R^(a).24 B-713-R^(a).24 B-72 4-R^(a).24 B-73 2-R^(a).25 B-74 3-R^(a).25 B-754-R^(a).25 B-76 2-R^(a).26 B-77 3-R^(a).26 B-78 4-R^(a).26 B-792-R^(a).27 B-80 3-R^(a).27 B-81 4-R^(a).27 B-82 2-R^(a).28 B-833-R^(a).28 B-84 4-R^(a).28 B-85 2-R^(a).29 B-86 3-R^(a).29 B-874-R^(a).29 B-88 2-R^(a).30 B-89 3-R^(a).30 B-90 4-R^(a).30 B-912-R^(a).31 B-92 3-R^(a).31 B-93 4-R^(a).31 B-94 2-R^(a).32 B-953-R^(a).32 B-96 4-R^(a).32 B-97 2-R^(a).33 B-98 3-R^(a).33 B-994-R^(a).33 B-100 2-R^(a).34 B-101 3-R^(a).34 B-102 4-R^(a).34 B-1032-R^(a).35 B-104 3-R^(a).35 B-105 4-R^(a).35 B-106 2-R^(a).36 B-1073-R^(a).36 B-108 4-R^(a).36 B-109 2-R^(a).37 B-110 3-R^(a).37 B-1114-R^(a).37 B-112 2-R^(a).38 B-113 3-R^(a).38 B-114 4-R^(a).38 B-1152-R^(a).39 B-116 3-R^(a).39 B-117 4-R^(a).39 B-118 2-R^(a).40 B-1193-R^(a).40 B-120 4-R^(a).40 B-121 2-R^(a).41 B-122 3-R^(a).41 B-1234-R^(a).41 B-124 2-R^(a).42 B-125 3-R^(a).42 B-126 4-R^(a).42 B-1272-R^(a).43 B-128 3-R^(a).43 B-129 4-R^(a).43 B-130 2-R^(a).44 B-1313-R^(a).44 B-132 4-R^(a).44 B-133 2-R^(a).45 B-134 3-R^(a).45 B-1354-R^(a).45 B-136 2-R^(a).46 B-137 3-R^(a).46 B-138 4-R^(a).46 B-1392-R^(a).47 B-140 3-R^(a).47 B-141 4-R^(a).47 B-142 2-R^(a).48 B-1433-R^(a).48 B-144 4-R^(a).48 B-145 2-R^(a).49 B-146 3-R^(a).49 B-1474-R^(a).49 B-148 2-R^(a).50 B-149 3-R^(a).50 B-150 4-R^(a).50 B-1512-R^(a).51 B-152 3-R^(a).51 B-153 4-R^(a).51 B-154 2-R^(a).52 B-1553-R^(a).52 B-156 4-R^(a).52 B-157 2-R^(a).53 B-158 3-R^(a).53 B-1594-R^(a).53 B-160 2-R^(a).54 B-161 3-R^(a).54 B-162 4-R^(a).54 B-1632-R^(a).55 B-164 3-R^(a).55 B-165 4-R^(a).55 B-166 2-R^(a).56 B-1673-R^(a).56 B-168 4-R^(a).56 B-169 2-R^(a).57 B-170 3-R^(a).57 B-1714-R^(a).57 B-172 2-R^(a).58 B-173 3-R^(a).58 B-174 4-R^(a).58 B-1752-R^(a).59 B-176 3-R^(a).59 B-177 4-R^(a).59 B-178 2-R^(a).60 B-1793-R^(a).60 B-180 4-R^(a).60

Among the above compounds, preference is given to compounds I.a.

In a specific embodiment, the invention relates to compounds I selectedfrom the compounds of the examples, either in form of free bases or ofany pharmaceutically acceptable salt thereof or a stereoisomer, theracemate or any mixture of stereoisomers thereof or a tautomer or atautomeric mixture or an N-oxide thereof.

The compounds of the present invention can be prepared by using routinetechniques familiar to a skilled person. In particular, the compounds ofthe formula I can be prepared according to the following schemes,wherein the variables, if not stated otherwise, are as defined above.

Compounds of the formula I wherein R¹ is R^(a) (termed in the followingcompounds I′) can be prepared, for example, starting from quinolinecompounds 1 which are substituted in 8-position by a leaving group X,such as a halogen atom, e.g. F, Cl, Br or I, in particular F, or asulfonate, such as triflate, nonaflate or tosylate, and heterocycliccompound R^(a)—H in a coupling reaction in the presence of a baseaccording to standard processes, e.g. according to the processesdescribed in WO 2005/113539 or US 2007/0027161, or without a base in apolar aprotic solvent such as dimethyl sulfoxide (DMSO) as described inBioorg. Med. Chem. Lett., 2003, 13, 1329. The coupling reaction isdepicted in scheme 1.

Suitable bases include alkali metal carbonates, such as lithiumcarbonate, sodium carbonate, potassium carbonate, alkalimetal hydroxidessuch as lithium hydroxide, sodium hydroxide and potassium hydroxide,alkalimetal alkoxides such as, sodium methoxide, sodium ethoxide, sodiumpropoxide, sodium n-butoxide, sodium tert.-butoxide, lithium methoxide,lithium ethoxide, lithium propoxide, lithium n-butoxide, lithiumtert.-butoxide, potassium methoxide, potassium ethoxide, potassiumpropoxide, potassium n-butoxide, potassium tert.-butoxide, alkalimetalhydrides such as lithium hydride, sodium hydride or potassium hydride.The amount of base is preferably at least 0.9 mol per mol of amine III,in particular at least 1.0 mol per mol of amine III, e.g. from 1.1 to 10mol per mol of amine III.

Suitable bases can be inorganic or organic. Examples for suitableinorganic bases are alkali metal carbonates, e.g. Li₂CO₃, Na₂CO₃, K₂CO₃or Cs₂CO₃, alkali metal hydroxides, e.g. LiOH, NaOH or KOH, orphosphates, e.g. Li₃PO₄, Na₃PO₄, K₃PO₄ or Cs₃PO₄. Examples for suitableorganic bases are open-chained amines, e.g. trimethylamine,triethylamine, tripropylamine, ethyldiisopropylamine and the like, basicN-heterocycles, such as morpholine, pyridine, lutidine, DABCO, DBU orDBN, alkoxylates, e.g. sodium or potassium methanolate, ethanolate,propanolate, isopropanolate, butanolate or tert-butanolate, especiallysterically hindered alkoxylates, such as sodium or potassiumtert-butanolate, silanolates, like sodium or potassiumtrimethylsilanolate ((CH₃)₃SiO⁻) or triisopropylsilanolate((CH(CH₃)₂)₃SiO⁻), phosphazene bases (superbases), such as BEMP andt-Bu-P4

or phenolates, especially sterically hindered phenolates, like thesodium or potassium salts of the following hydroxyaromatic compounds:

wherein R is H or optionally substituted C₁-C₂-alkyl, e.g. methyl,CH₂—N(CH₃)₂ or CH₂CH₂—C(O)—O—C₁₈H₂₁. Specifically, inorganic bases, suchas the alkali metal carbonates, e.g. Li₂CO₃, Na₂CO₃, K₂CO₃ or Cs₂CO₃,are used.

Generally, the coupling reaction is performed in an inert solvent.Suitable inert solvents include aromatic hydrocarbons, such as benzene,toluene, the xylenes, ethylbenzene, isopropylbenzene, butylbenzene,tert.-butylbenzene, chlorobenzene, the dichlorobenzenes or anisol,aliphatic or alicyclic ethers, such as tetrahydrofuran,methyltetrahydrofuran or dioxane, aliphatic or alicyclic sulfones andsulfoxides, such as dimethyl sulfoxide, sulfolane and the like, andN,N-dialkylamides of aliphatic C₁-C₃-carboxylic acides andN-alkyllactames, such as dimethyl formamide, dimethyl acetamide,N-methylpyrrolidon, N-methylpiperidone, or N-ethylpyrrolidone.

If the (hetero)aromatic ring R² carries a substituent R⁵ which cancompete in this reaction (e.g. if R⁵ is a halogen atom which is asreactive as X or even more reactive), compounds I can form in whichR^(a) is bound to the (hetero)aromatic ring R² instead of the 8-positionof the quinoline scaffold (termed in the following compounds I″).Moreover, compounds I can form in which R^(a) is bound both to the8-position of the quinoline ring and to the (hetero)aromatic ring R²(termed in the following compounds I′″). Compounds I′, I″ and I′″ can beseparated from each other by standard procedures, e.g. bychromatographic methods. If the formation of compounds I″ and I′″ is tobe prevented, R⁵, if present, has to be unreactive towards R^(a)—H underthe given conditions or at least significantly less reactive than X.

If inversely compounds I″ are to be obtained, in which R^(a) is bound tothe (hetero)aromatic ring R² instead of the 8-position of the quinolinescaffold, the starting compound 2 expediently carries as radical R¹ asubstituent which is unreactive towards R^(a)—H under the givenconditions or at least significantly less reactive than X. X in scheme 2is, like in scheme 1, a leaving group, such as a halogen atom, e.g. F,Cl, Br or I, or a sulfonate, such as triflate, nonaflate or tosylate.R²′ is R² without the desired R^(a) substituent.

In the above reactions, R³, if present, is expediently unreactivetowards R^(a)—H under the given conditions or at least significantlyless reactive than X. Otherwise R^(a) may be bound in the position of R³instead of that of X.

The ring R^(a) may also be introduced in a Buchwald-Hartwig reaction. Inthis context, the starting compounds 1 or 2 are reacted with R^(a)—H inthe presence of a transition metal-catalyst, mostly a Pd catalyst, andgenerally also in the presence of a base. In compounds 1 or 2 X is inparticular Cl, Br or I.

The Pd catalyst can generally either be used as a salt (e.g. Pd(II)acetate or Na₂PdCl₄) or, more often, as a Pd(II) complex which is eitherpreformed or prepared in situ from a Pd(II) salt (e.g. Pd(II)acetate orPdCl2) and the respective ligand. The same applies to Ni catalysts.Suitable ligands for the complex often contain phosphorus. Examples forphosphorus ligands aredi-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)-phosphine (cBRIDP;Mo-Phos), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (t-BuXPhos, tBuXPhos, tert-Butyl XPhos), 1,1′-bis(diphenylphosphino)ferrocene(dppf), 1,1′-bis(di-tert-butylphosphino)ferrocene (dtbpf),1,2-bis(diphenylphosphino)-ethane (dppe),1,3-bis(diphenylphosphino)-propane (dppp),1,4-bis(diphenyl-phosphino)butane (dppb),(2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenyl-phosphino)butane(diop), bis(di-tert-butyl(4-dimethylaminophenyl)-phosphine) (Amphos),(2S,3S)-(−)-bis(diphenylphosphino)butane (Chiraphos),di-(tert-butyl)phenylphosphine,2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP),[1,1′-biphenyl]-2-diisopropyl phosphine,2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-phos),9,9-dimethyl-4,5-bis(diphenyl-phosphino)xanthene (Xantphos),4,5-bis-(di-1-(3-methylindolyl)-phosphoramidit)-2,7,9,9-tetramethyl-xanthene(MeSkatOX), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-phos),2-(2-dicyclohexyl-phosphanylphenyl)-N1,N1,N3,N3-tetramethyl-benzene-1,3-diamine(C-phos),6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(bis(3,5-dimethylphenyl)phosphine,[(4R)-(4,4′-bis-1,3-benzodioxole)-5,5′-diyl]bis[bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphine]((R)-DTBM-SEGPHOS®), (R)- or (S)-3,5-Xyl-MeO-BIPHEP, (R,S)— or(S,R)—PPF—P(t-Bu)₂, the Josiphos ligands, triphenylphosphine,triphenylphosphite,tri-(2-(1,1-dimethylethyl)-4-methoxy-phenyl)-phosphite,tricyclohexylphosphine, tri(tert-butyl)phosphine,butyldi-1-adamantylphosphine (cataCXium),1,6-bis(diphenylphosphino)hexane (DPPH),2,6-bis(2,5-dimethylphenyl)-1-octyl-4-phenylphosphacyclohexan (PCH),tris(3-sulfophenyl)phosphine trisodium salt (TPPTS) and the like.

Non-phosphorus ligands are for example bis(dibenzylideneacetone) (dba),acetonitrile, bisoxazoline and the like. Further, examples for Pdcatalysts with ligands without phosphorus are the PEPPSI catalysts(PEPPSI=Pyridine-Enhanced Precatalyst Preparation Stabilization andInitiation)

in which R is a small organic fragment, e.g. methyl, ethyl, isopropyl,isopentyl, or isoheptyl. The corresponding catalysts are labeled asPEPPSI-IMes, PEPPSI-IEt, PEPPSI-IPr, PEPPSI-IPent, and PEPPSI-IHeptrespectively, with or without “Pd—” added in front.

Also new generation PEPPSI catalysts are suitable:

Here, too, R is a small organic fragment, e.g. methyl, ethyl, isopropyl,isopentyl, or isoheptyl.

The catalyst is generally used in catalytic, i.e. substoichiometricamounts, e.g. in an amount of from 0.001 to 0.5 mol per mol of thatreactant which is not used in excess.

Suitable bases are those mentioned above.

Compounds 1 and 2 are either commercially available or can be preparedby standard reactions, such as described, for example, in WO 2003/080580or WO 2009/019286.

For instance, compounds 1 and 2 wherein L is S(O)₂ (termed hereinaftercompounds 1′ and 2′) can be prepared as outlined in schemes 3 and 4 byreacting the iodide 3 or 5 with the sulfinate 4 or 6. M⁺ is a metalcation equivalent, such as Li⁺, Na⁺ or K⁺, or is an ammonium cation(NH₄) or a substituted ammonium cation. The reaction is generallycarried out in the presence of a transition metal catalyst, especially aCu(I) catalyst, such as Cu (I) triflate, generally in a polar solvent,such as N,N-dimethyl acetamide (DMA) or DMF. In 3 X has to less reactivethan I towards the sulfinate 4, and is for example F, Cl or Br.

For preparing compounds 1′ wherein X is I, the nitro compound 7 can beused as starting material, as shown in scheme 5 below. After conversionto 8 in analogy to the reaction in scheme 3 or 4 the nitro group isreduced and the amino group is then submitted to a substitution reactionto yield 1′ with X═I. Reduction can be achieved by a variety of methods,including reduction with “non-hydrogen” reducing agents such as SnCl₂,or by catalytic hydrogenation techniques familiar to those skilled inthe art. For substituting the amino group by I, a Sandmeyer reaction canbe carried out, using a nitrosonium source (e.g. NaNO₂, nBuNO₂) and aiodide (e.g. CuI or n-Bu₄NI) in a suitable solvent, such water or CH₃CN.

The sulfonates 4 and 6 can be obtained, for example, by reacting thecorresponding sulfonyl chlorides (R²—S(O)₂—Cl or X—R²′—S(O)₂—C1) with areducing agent and neutralizing the sulfinic acid formed. For instance,the sulfite of M+, e.g. sodium sulfite, can be used, if desired in thepresence of a base.

Compounds 1 and 2 wherein L is NH—S(O)₂ (termed hereinafter compounds 1″and 2″) can be prepared as outlined in schemes 6 and 7 by reacting theamine 10 or 12 with the sulfonyl chloride 11 or 13.

Compounds 1 and 2 wherein L is S(O)₂—NH (termed hereinafter compounds1′″ and 2′″) can be prepared as outlined in schemes 8 and 9 by reactingthe sulfonyl chloride 10 or 16 with the amine 15 or 17.

The reactions in schemes 6 to 9 are generally carried out in thepresence of a base. Suitable bases are those listed above.

Compounds 1 and 2 wherein L is C(O)—NH can be prepared in analogy toschemes 6 and 7, where however instead of the sulfonyl chloride 11 and13 a suitable carbonyl compound is used. Suitable carbonyl compounds aree.g. the respective carboxylic acids (R²—C(O)OH or X—R²′—C(O)OH),carbonyl chlorides (R²—C(O)Cl or X—R²′—C(O)C1), esters (R²—C(O)OR orX—R²′—C(O)OR), or anhydrides (R²—C(O)OC(O)—R′ or X—R²′—C(O)OC(O)R′).

If a carboxylic acid is used, the reaction is generally carried out inthe presence of a coupling reagent. Suitable coupling reagent(activators) are well known and are for instance selected from the groupconsisting of carbodiimides, such as EDCI(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; also abbreviated asEDC), DCC (dicyclohexylcarbodiimide) and DIC (diisopropylcarbodiimide),benzotriazole derivatives, such as HOBt (1-hydroxybenzotriazole), HATU(O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate), HBTU((O-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate)and HCTU (1H-benzotriazolium-1-[bis(dimethylamino)methylene]-5-chlorotetrafluoroborate), phosphonium-derived activators, such as BOP((benzotriazol-1-yloxy)-tris(dimethylamino)phosphoniumhexafluorophosphate), Py-BOP((benzotriazol-1-yloxy)-tripyrrolidinphosphonium hexafluorophosphate)and Py-BrOP (bromotripyrrolidinphosphonium hexafluorophosphate), andothers, such as COMU((1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium-hexafluorophosphat).The above activators can also be used in combination with each other.Generally, the activator is used in at least equimolar amounts, withrespect to that reactant not used in excess. The benzotriazole andphosphonium coupling reagents are generally used in a basic medium.

Suitable esters derive expediently from C₁-C₄-alkanols ROH in which R isC₁-C₄-alkyl, such as methanol, ethanol, propanol, isopropanol,n-butanol, butan-2-ol, isobutanol and tert-butanol, preference beinggiven to the methyl and ethyl esters (R=methyl or ethyl). Suitableesters may also derive from C₂-C₆-polyols such as glycol, glycerol,trimethylolpropane, erythritol, pentaerythritol and sorbitol, preferencebeing given to the glyceryl ester. When polyol esters are used, it ispossible to use mixed esters, i.e. esters with different R radicals.

Alternatively, the ester is a so-called active ester, which is obtainedin a formal sense by the reaction of the carboxylic acid with an activeester-forming alcohol, such as p-nitrophenol, N-hydroxybenzotriazole(HOBt), N-hydroxysuccinimide or OPfp (pentafluorophenol).

The acid anhydride is either a symmetric anhydride R²—C(O)OC(O)—R² orX—R²′—C(O)OC(O)R²′—X or an asymmetric anhydride in which —O—OC— R¹ is agroup which can be displaced easily by the amino group. Suitable acidderivatives with which the carboxylic acid can form suitable mixedanhydrides are, for example, the esters of chloroformic acid, forexample isopropyl chloroformate and isobutyl chloroformate, or ofchloroacetic acid.

If a carbonyl chloride is used, the reaction is generally carried out inthe presence of a base. Suitable bases are those listed above.

Compounds 1 and 2 wherein L is a chemical bond can for example beprepared by various C—C coupling reactions of the suitable R² or X—R²′derivative and the quinoline derivative. A suitable coupling reaction isfor example the Suzuki reaction. For example, compound 3, 5 or 7 can bereacted with the suitable boronic ester of R² or X—R²′.

Compounds 1 and 2 wherein L is an ethynyl bridge can be prepared, forexample, via a Sonogashira reaction, e.g. by reacting a compound 3, 5 or7 with HC≡C—R² or HC≡C—R²′—X in the presence of a suitable catalyst.

If not indicated otherwise, the above-described reactions are generallycarried out in a solvent at temperatures between room temperature andthe boiling temperature of the solvent employed. Alternatively, theactivation energy which is required for the reaction can be introducedinto the reaction mixture using microwaves, something which has provedto be of value, in particular, in the case of the reactions catalyzed bytransition metals (with regard to reactions using microwaves, seeTetrahedron 2001, 57, p. 9199 ff. p. 9225 ff. and also, in a generalmanner, “Microwaves in Organic Synthesis”, André Loupy (Ed.), Wiley-VCH2002.

The acid addition salts of compounds I are prepared in a customarymanner by mixing the free base with a corresponding acid, whereappropriate in solution in an organic solvent, for example acetonitrile,a lower alcohol, such as methanol, ethanol or propanol, an ether, suchas diethyl ether, methyl tert-butyl ether or diisopropyl ether, aketone, such as acetone or methyl ethyl ketone, an ester, such as ethylacetate, mixtures thereof as well as mixtures thereof with water.

The present invention moreover relates to compounds of formula I asdefined above, wherein at least one of the atoms has been replaced byits stable, non-radioactive isotope (e.g., hydrogen by deuterium, ¹²C by¹³C, ¹⁴N by ¹⁵N, ¹⁶O by ¹⁸O) and preferably wherein at least onehydrogen atom has been replaced by a deuterium atom.

Of course, the unlabelled compounds according to the invention mightnaturally include certain amounts of these respective isotopes.Therefore, when referring to compounds I, wherein at least one of theatoms has been replaced by its stable, non-radioactive isotope, it willbe understood that the isotope is present in a higher amount than wouldnaturally occur.

Stable isotopes (e.g., deuterium, ¹³C, ¹⁵N, ¹⁸O) are nonradioactiveisotopes which contain one additional neutron than the normally abundantisotope of the respective atom. Deuterated compounds have been used inpharmaceutical research to investigate the in vivo metabolic fate of thecompounds by evaluation of the mechanism of action and metabolic pathwayof the non deuterated parent compound (Blake et al. J. Pharm. Sci. 64,3, 367-391 (1975)). Such metabolic studies are important in the designof safe, effective therapeutic drugs, either because the in vivo activecompound administered to the patient or because the metabolites producedfrom the parent compound prove to be toxic or carcinogenic (Foster etal., Advances in Drug Research Vol. 14, pp. 2-36, Academic press,London, 1985; Kato et al., J. Labelled Comp. Radiopharmaceut.,36(10):927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacol., 77,79-88 (1999).

Incorporation of a heavy atom, particularly substitution of deuteriumfor hydrogen, can give rise to an isotope effect that could alter thepharmacokinetics of the drug.

Stable isotope labeling of a drug can alter its physico-chemicalproperties such as pKa and lipid solubility. These changes may influencethe fate of the drug at different steps along its passage through thebody. Absorption, distribution, metabolism or excretion can be changed.Absorption and distribution are processes that depend primarily on themolecular size and the lipophilicity of the substance. These effects andalterations can affect the pharmacodynamic response of the drug moleculeif the isotopic substitution affects a region involved in aligand-receptor interaction.

Drug metabolism can give rise to large isotopic effect if the breakingof a chemical bond to a deuterium atom is the rate limiting step in theprocess. While some of the physical properties of a stableisotope-labeled molecule are different from those of the unlabeled one,the chemical and biological properties are the same, with one importantexception: because of the increased mass of the heavy isotope, any bondinvolving the heavy isotope and another atom will be stronger than thesame bond between the light isotope and that atom. In any reaction inwhich the breaking of this bond is the rate limiting step, the reactionwill proceed slower for the molecule with the heavy isotope due to“kinetic isotope effect”. A reaction involving breaking a C-D bond canbe up to 700 percent slower than a similar reaction involving breaking aC—H bond. If the C-D bond is not involved in any of the steps leading tothe metabolite, there may not be any effect to alter the behavior of thedrug. If a deuterium is placed at a site involved in the metabolism of adrug, an isotope effect will be observed only if breaking of the C-Dbond is the rate limiting step. There is evidence to suggest thatwhenever cleavage of an aliphatic C—H bond occurs, usually by oxidationcatalyzed by a mixed-function oxidase, replacement of the hydrogen bydeuterium will lead to observable isotope effect. It is also importantto understand that the incorporation of deuterium at the site ofmetabolism slows its rate to the point where another metabolite producedby attack at a carbon atom not substituted by deuterium becomes themajor pathway a process called “metabolic switching”.

Deuterium tracers, such as deuterium-labeled drugs and doses, in somecases re-peatedly, of thousands of milligrams of deuterated water, arealso used in healthy humans of all ages, including neonates and pregnantwomen, without reported incident (e.g. Pons G and Rey E, Pediatrics 1999104: 633; Coward W A et al., Lancet 1979 7: 13; Schwarcz H P, Control.Clin. Trials 1984 5(4 Suppl): 573; Rodewald L E et al., J. Pediatr. 1989114: 885; Butte N F et al. Br. J. Nutr. 1991 65: 3; MacLennan A H et al.Am. J. Obstet Gynecol. 1981 139: 948). Thus, it is clear that anydeuterium released, for instance, during the metabolism of compounds ofthis invention poses no health risk.

The weight percentage of hydrogen in a mammal (approximately 9%) andnatural abundance of deuterium (approximately 0.015%) indicates that a70 kg human normally contains nearly a gram of deuterium. Furthermore,replacement of up to about 15% of normal hydrogen with deuterium hasbeen effected and maintained for a period of days to weeks in mammals,including rodents and dogs, with minimal observed adverse effects(Czajka D M and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770; Thomson JF, Ann. New York Acad. Sci 1960 84: 736; Czakja D M et al., Am. J.Physiol. 1961 201: 357). Higher deuterium concentrations, usually inexcess of 20%, can be toxic in animals. However, acute replacement of ashigh as 15%-23% of the hydrogen in humans' fluids with deuterium wasfound not to cause toxicity (Blagojevic N et al. in “Dosimetry &Treatment Planning for Neutron Capture Therapy”, Zamenhof R, Solares Gand Harling O Eds. 1994. Advanced Medical Publishing, Madison Wis. pp.125-134; Diabetes Metab. 23: 251 (1997)).

Increasing the amount of deuterium present in a compound above itsnatural abundance is called enrichment or deuterium-enrichment. Examplesof the amount of enrichment include from about 0.5, 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71,75, 79, 84, 88, 92, 96, to about 100 mol %.

The hydrogens present on a particular organic compound have differentcapacities for exchange with deuterium. Certain hydrogen atoms areeasily exchangeable under physiological conditions and, if replaced bydeuterium atoms, it is expected that they will readily exchange forprotons after administration to a patient. Certain hydrogen atoms may beexchanged for deuterium atoms by the action of a deuteric acid such asD₂SO₄/D₂O. Alternatively, deuterium atoms may be incorporated in variouscombinations during the synthesis of compounds of the invention. Certainhydrogen atoms are not easily exchangeable for deuterium atoms. However,deuterium atoms at the remaining positions may be incorporated by theuse of deuterated starting materials or intermediates during theconstruction of compounds of the invention.

Deuterated and deuterium-enriched compounds of the invention can beprepared by using known methods described in the literature. Suchmethods can be carried out utilizing corresponding deuterated andoptionally, other isotope-containing reagents and/or intermediates tosynthesize the compounds delineated herein, or invoking standardsynthetic protocols known in the art for introducing isotopic atoms to achemical structure. Relevant procedures and intermediates are disclosed,for instance in Lizondo, J et al., Drugs Fut, 21(11), 1116 (1996);Brickner, S J et al., J Med Chem, 39(3), 673 (1996); Mallesham, B etal., Org Lett, 5(7), 963 (2003); PCT publications WO 1997010223,WO2005099353, WO 1995007271, WO2006008754; U.S. Pat. Nos. 7,538,189;7,534,814; 7,531,685; 7,528,131; 7,521,421; 7,514,068; 7,511,013; and USPatent Application Publication Nos. 20090137457; 20090131485;20090131363; 20090118238; 20090111840; 20090105338; 20090105307;20090105147; 20090093422; 20090088416; 20090082471, the methods arehereby incorporated by reference.

The present invention further relates to a pharmaceutical compositioncomprising at least one compound of formula I, a stereoisomer, prodrug,tautomer and/or physiologically tolerated acid addition salt thereof andoptionally at least one physiologically acceptable carrier and/orauxiliary substance.

The invention relates moreover to the use of compounds of formula I orof a stereoisomer, N-oxide, prodrug, tautomer or physiologicallytolerated acid addition salt thereof or of a compound of formula I,wherein at least one of the atoms has been replaced by its stable,non-radioactive isotope, for the preparation of a medicament for thetreatment of a medical disorder susceptible to the treatment with a5-HT₆ receptor ligand, and to a method for treating a medical disordersusceptible to the treatment with a 5-HT₆ receptor ligand, said methodcomprising administering an effective amount of at least one compound offormula I or of a stereoisomer, N-oxide, prodrug, tautomer orphysiologically tolerated acid addition salt thereof or of a compound offormula I, wherein at least one of the atoms has been replaced by itsstable, non-radioactive isotope, or of a pharmaceutical composition asdefined above to a subject in need thereof.

The present invention also relates to the compounds of formula I or astereoisomer, N-oxide, prodrug, tautomer or physiologically toleratedacid addition salt thereof or a compound of formula I, wherein at leastone of the atoms has been replaced by its stable, non-radioactiveisotope, for use in modulating the 5-HT₆ receptor.

The compounds of the present invention can be a 5-HT₆ receptor agonist,including partial agonistic activity, or a 5-HT₆ receptor antagonist,including inverse agonist activity.

The compounds according to the present invention, as well as their saltsand their N-oxides, have a surprisingly high affinity for 5-HT₆receptors. The high affinity of the compounds according to the inventionfor 5-HT₆ receptors is reflected in very low in-vitro receptor bindingconstants (K_(i)(5-HT₆) values) of as a rule less than 500, 100 or 50 nM(nmol/l), preferably of less than 10 nM and, in particular of less than5 nM. The displacement of ³H-LSD can, for example, be used in receptorbinding studies for determining binding affinities to 5-HT₆ receptors.

Furthermore the compounds of the invention, as well as their salts andtheir N-oxides, are highly selective 5-HT₆ receptor ligands which,because of their low affinity for other receptors such as dopaminereceptors, adrenergic receptors, muscarinic receptors, histaminereceptors, opiate receptors, in particular dopamine D₂, α₁-adrenergicand histamine H₁ receptors, give rise to fewer side-effects than other,less selective 5-HT₆ ligands.

For instance the 5-HT₆/D₂, 5-HT₆/α₁-adrenergic or 5-HT₆/H₁ selectivitiesof the compounds according to the present invention, i.e. the ratiosK_(i)(D₂)/K_(i)(5-HT₆), K_(i)(α₁-adrenergic)/K_(i)(5-HT₆) orK_(i)(H₁)/K_(i)(5-HT₆) of the receptor binding constants, is as a ruleat least 25, preferably at least 50, even better at least 100.

The displacement of [³H]SCH23390 or [¹²⁵I]spiperone can be used, forexample, for carrying out receptor binding studies on D₁, D₂ and D₄receptors.

Furthermore the compounds of the present invention because of theirstructural features are susceptible to display an enhanced brainpenetration than other known 5-HT₆ receptor ligands.

Moreover, the compounds of the present invention because of theirstructural features show no or only low blockade of the hERG channel.

Because of their binding profile, the compounds of the present inventioncan be used for treating diseases which respond to 5-HT₆ receptorligands (or which are susceptible to treatment with a 5-HT₆ receptorligand), i.e. they are effective for treating those medical disorders ordiseases in which exerting an influence on (modulating) the 5-HT₆receptor leads to an improvement in the clinical picture or to thedisease being cured. Examples of these diseases are disorders ordiseases of the central nervous system.

Disorders or diseases of the central nervous system are understood asmeaning disorders which affect the spinal cord and, in particular, thebrain. Within the meaning of the invention, the term “disorder” denotesdisturbances and/or anomalies which are as a rule regarded as beingpathological conditions or functions and which can manifest themselvesin the form of particular signs, symptoms and/or malfunctions. While thetreatment according to the invention can be directed toward individualdisorders, i.e. anomalies or pathological conditions, it is alsopossible for several anomalies, which may be causatively linked to eachother, to be combined into patterns, i.e. syndromes, which can betreated in accordance with the invention.

The disorders which can be treated in accordance with the invention arein particular disorders which respond to a modulation of the 5-HT₆receptor. They include cognitive dysfunctions, such as a deficit inmemory, cognition and learning, in particular associated withAlzheimer's disease, age-related cognitive decline and mild cognitiveimpairment, attention deficit disorder/hyperactivity syndrome,personality disorders, such as schizophrenia, in particular cognitivedeficits related with schizophrenia, affective disorders such asdepression, anxiety and obsessive compulsive disorders, motion or motordisorders such as Parkinson's disease and epilepsy, migraine, sleepdisorders (including disturbances of the Circadian rhythm), feedingdisorders, such as anorexia and bulimia, certain gastrointestinaldisorders such as Irritable Bowel Syndrome, diseases associated withneurodegeneration, such as stroke, spinal or head trauma and headinjuries, such as hydrocephalus, addiction diseases including e.g. drugaddiction and obesity.

The addiction diseases include psychic disorders and behavioraldisturbances which are caused by the abuse of psychotropic substances,including certain pharmaceuticals, such as sedative, anxiolytica,hypnotics or narcotics (hereinafter also referred to as drug addiction),and also other addiction diseases, such as addiction to gaming(gambling; impulse control disorders not elsewhere classified). Examplesof addictive substances are: opioids (e.g. morphine, heroin andcodeine), cocaine; nicotine; alcohol; substances which interact with theGABA chloride channel complex, sedatives, hypnotics and tranquilizers,for example benzodiazepines; LSD; cannabinoids; psychomotor stimulants,such as 3,4-methylenedioxy-N-methylamphetamine (ecstasy); amphetamineand amphetamine-like substances such as methylphenidate and otherstimulants including caffeine. Addictive substances which comeparticularly into consideration are opioids, cocaine, amphetamine oramphetamine-like substances, hallucinogens, NMDA-receptor antagonistssuch phencyclidine and related cyclidines, dextrometorphan, dextrorphan,ibogaine, ketimine and tiletamine, cannabis, nicotine and alcohol. Otheraddiction diseases include gaming (gambling), including problem gambling(compulsive gambling, ludomania), computer or video game addiction andinternet addiction.

With regard to the treatment of addiction diseases, particularpreference is given to those compounds according to the presentinvention which themselves do not possess any psychotropic effect. Thiscan also be observed in a test using rats, which, after having beenadministered compounds which can be used in accordance with theinvention, reduce their self administration of psychotropic substances,for example cocaine or alcohol.

According to another aspect of the present invention, the compoundsaccording to the invention are suitable for treating disorders whosecauses can at least partially be attributed to an anomalous activity of5-HT₆ receptors.

According to another aspect of the present invention, the treatment isdirected, in particular, toward those disorders which can be influenced,within the sense of an expedient medicinal treatment, by the binding ofpreferably exogeneously administered binding partners (ligands) to 5-HT₆receptors.

The diseases which can be treated with the compounds according to theinvention are frequently characterized by progressive development, i.e.the above-described conditions change over the course of time; as arule, the severity increases and conditions may possibly merge into eachother or other conditions may appear in addition to those which alreadyexist.

The compounds of the present invention can be used to treat a largenumber of signs, symptoms and/or malfunctions which are connected withthe disorders of the central nervous system and, in particular, theabovementioned conditions. These signs, symptoms and/or malfunctionsinclude, for example, a disturbed relationship to reality, lack ofinsight and ability to meet customary social norms or the demands madeby life, changes in temperament, changes in individual drives, such ashunger, sleep, thirst, etc., and in mood, disturbances in the ability toobserve and combine, changes in personality, in particular emotionallability, hallucinations, ego-disturbances, distractedness, ambivalence,autism, depersonalization and false perceptions, delusional ideas,chanting speech, lack of synkinesia, short-step gait, flexed posture oftrunk and limbs, tremor, poverty of facial expression, monotonousspeech, depressions, apathy, impeded spontaneity and decisiveness,impoverished association ability, anxiety, nervous agitation,stammering, social phobia, panic disturbances, withdrawal symptoms inassociation with dependency, maniform syndromes, states of excitationand confusion, dysphoria, dyskinetic syndromes and tic disorders, e.g.Huntington's chorea and Gilles-de-la-Tourette's syndrome, vertigosyndromes, e.g. peripheral positional, rotational and oscillatoryvertigo, melancholia, hysteria, hypochondria and the like.

Within the meaning of the invention, a treatment also includes apreventive treatment (prophylaxis), in particular as relapse prophylaxisor phase prophylaxis, as well as the treatment of acute or chronicsigns, symptoms and/or malfunctions. The treatment can be orientatedsymptomatically, for example as the suppression of symptoms. It can beeffected over a short period, be orientated over the medium term or canbe a long-term treatment, for example within the context of amaintenance therapy.

The compounds according to the invention are preferentially suitable fortreating diseases of the central nervous system, more preferably fortreating cognitive dysfunctions and in particular, for treatingcognitive dysfunctions associated with schizophrenia or with Alzheimer'sdisease.

According to another aspect of the invention the compounds of thepresent invention are particularly suitable for treating addictiondiseases caused for instance by the abuse of psychotropic substances,such as pharmaceuticals, narcotics, nicotine or alcohol, includingpsychic disorders and behavioral disturbances related thereto. Thecompounds of the present invention are likewise particularly suitablefor treating addiction diseases which are not caused by the abuse ofpsychotropic substances, such as gaming (gambling), including problemgambling (compulsive gambling, ludomania), computer or video gameaddiction and internet addiction. With regard to addiction diseases, thecompound of the present invention can be used for the therapy duringaddiction and also for preventing relapse into addiction.

According to another aspect of the invention the compounds of theinvention, their salts and their N-oxides are particularly suitable fortreating nutritional disorders, such as obesity, as well as diseasesrelated thereto, such as cardiovascular diseases, digestive diseases,respiratory diseases, cancer or type 2 diabetes.

Within the context of the treatment, the use according to the inventionof the described compounds involves a method. In this method, aneffective quantity of one or more compounds, as a rule formulated inaccordance with pharmaceutical and veterinary practice, is administeredto the individual to be treated, preferably a mammal, in particular ahuman being, productive animal or domestic animal. Whether such atreatment is indicated, and in which form it is to take place, dependson the individual case and is subject to medical assessment (diagnosis)which takes into consideration signs, symptoms and/or malfunctions whichare present, the risks of developing particular signs, symptoms and/ormalfunctions, and other factors.

As a rule, the treatment is effected by means of single or repeateddaily administration, where appropriate together, or alternating, withother active compounds or active compound-containing preparations suchthat a daily dose of preferably from about 0.1 to 1000 mg/kg ofbodyweight, in the case of oral administration, or of from about 0.1 to100 mg/kg of bodyweight, in the case of parenteral administration, issupplied to an individual to be treated.

The invention also relates to the production of pharmaceuticalcompositions for treating an individual, preferably a mammal, inparticular a human being, productive animal or domestic animal. Thus,the compounds of the invention, their salts and/or their N-oxides arecustomarily administered in the form of pharmaceutical compositionswhich comprise a pharmaceutically acceptable excipient together with atleast one compound according to the invention and, where appropriate,other active compounds. These compositions can, for example, beadministered orally, rectally, transdermally, subcutaneously,intravenously, intramuscularly or intranasally.

Examples of suitable pharmaceutical formulations are solid medicinalforms, such as powders, granules, tablets, in particular film tablets,lozenges, sachets, cachets, sugar-coated tablets, capsules, such as hardgelatin capsules and soft gelatin capsules, suppositories or vaginalmedicinal forms, semisolid medicinal forms, such as ointments, creams,hydrogels, pastes or plasters, and also liquid medicinal forms, such assolutions, emulsions, in particular oil-in-water emulsions, suspensions,for example lotions, injection preparations and infusion preparations,and eyedrops and eardrops. Implanted release devices can also be usedfor administering inhibitors according to the invention. In addition, itis also possible to use liposomes or microspheres.

When producing the compositions, the compounds according to theinvention are optionally mixed or diluted with one or more excipients.Excipients can be solid, semisolid or liquid materials which serve asvehicles, carriers or medium for the active compound.

Suitable excipients are listed in the specialist medicinal monographs.In addition, the formulations can comprise pharmaceutically acceptablecarriers or customary auxiliary substances, such as glidants; wettingagents; emulsifying and suspending agents; preservatives; antioxidants;antiirritants; chelating agents; coating auxiliaries; emulsionstabilizers; film formers; gel formers; odor masking agents; tastecorrigents; resin; hydrocolloids; solvents; solubilizers; neutralizingagents; diffusion accelerators; pigments; quaternary ammonium compounds;refatting and overfatting agents; raw materials for ointments, creams oroils; silicone derivatives; spreading auxiliaries; stabilizers;sterilants; suppository bases; tablet auxiliaries, such as binders,fillers, glidants, disintegrants or coatings; propellants; dryingagents; opacifiers; thickeners; waxes; plasticizers and white mineraloils. A formulation in this regard is based on specialist knowledge asdescribed, for example, in Fiedler, H. P., Lexikon der Hilfsstoffe firPharmazie, Kosmetik und angrenzende Gebiete [Encyclopedia of auxiliarysubstances for pharmacy, cosmetics and related fields], 4^(th) edition,Aulendorf: ECV-Editio-Kantor-Verlag, 1996.

The following examples serve to explain the present invention withoutlimiting its scope.

EXAMPLES Abbreviations DMF N,N-dimethylformamide NMP N-methylpyrrolidone

MeOH methanolDCM dichloromethaneTFA trifluoroacetic aciddppf 1,1′-bis(diphenylphosphino)ferrocenBINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthylTLC thin liquid chromatographyPrep-TLC preparative TLCRf retention factorXphos Pd G2 catalyst (synonym: 2nd Generation XPhos Precatalyst,chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]-palladium(II), X-Phos aminobiphenylpalladium chloride precatalyst, XPhos-Pd-G2): catalyst of followingformula:

The compounds were either characterized via proton-NMR in deuteriumoxide, d₆-dimethylsulfoxide, d-chloroform or d₄-methanol on a 400 MHz,500 MHz or 600 MHz NMR instrument (Bruker AVANCE), or by massspectrometry, generally recorded via HPLC-MS in a fast gradient onC18-material (electrospray-ionisation (ESI) mode).

The magnetic nuclear resonance spectral properties (NMR) refer to thechemical shifts (6) expressed in parts per million (ppm). The relativearea of the shifts in the ¹H-NMR spectrum corresponds to the number ofhydrogen atoms for a particular functional type in the molecule. Thenature of the shift, as regards multiplicity, is indicated as singlet(s), broad singlet (br s), doublet (d), broad doublet (br d), triplet(t), broad triplet (br t), quartet (q), quintet (quint.), multiplet (m),broad multiplet (br m), doublet of doublets (dd), doublet of doublets ofdoublets (ddd), triplet of doublets (td), doublet of triplets ofdoublets (dtd), doublet of triplets of triplets (dtt), quartet ofdoublets of doublets (qdd) etc.

I. Preparation of the Compounds I Example 11-[3-(3-Trifluoromethyl-benzenesulfonyl)-quinolin-8-yl]-piperidin-4-ol

8-Fluoro-3-iodoquinoline (5.29 g, 19.38 mmol), sodium3-(trifluoromethyl)-benzenesulfinate (5.0 g, 19.38 mmol) andcopper(I)trifluoromethanesulfonate benzene complex (10.84 g, 19.38 mmol)were dissolved in DMF (80 ml) and warmed up to 65° C. for 14 h andstirred at room temperature overnight. The reaction mixture was filteredthrough a fritted funnel and concentrated under high vacuo. The residuewas dissolved in DCM and washed 5× with aqueous NH₄OH solution. Theorganic layer was dried and concentrated. The residue was purified usingflash chromatography (120 g column; cyclohexane 100%→cyclohexane:ethylacetate 20:80, 85 ml/min) to give8-fluoro-3-(3trifluoromethyl)phenylsulfonyl) quinolone (2.1 g, yield30.5%). 8-Fluoro-3-(3-(trifluoromethyl)phenylsulfonyl)quinoline (600 mg,1.689 mmol) and piperidin-4-ol (769 mg, 7.60 mmol) were suspended in NMP(18 ml) and K₂CO₃ (934 mg, 6.75 mmol) was added and stirred at 225° C.in Microwave for 40 min. The reaction mixture was diluted with ethylacetate and washed 4× with water, dried and concentrated. The residuewas purified using flash chromatography (DCM 100%→DCM:MeOH 98:2) to give1-(3-(3-(trifluoromethyl)phenylsulfonyl)quinolin-8-yl)piperidin-4-ol(290 mg, yield 39.3%).

LCMS (ESI⁺) m/z [M+H]⁺: 437.10

¹H NMR (DMSO-d₆, 500 MHz): δ=9.34 (d, J=2.1 Hz, 1H), 9.14 (d, J=2.1 Hz,1H), 8.44 (d, J=8.2 Hz, 1H), 8.41 (s, 1H), 8.13 (d, J=7.9 Hz, 1H), 7.91(t, J=7.9 Hz, 1H), 7.73-7.76 (m, J=8.2 Hz, 1H), 7.63 (t, J=7.9 Hz, 1H),7.33-7.36 (m, J=7.6 Hz, 1H), 4.70 (d, J=4.0 Hz, 1H), 3.63-3.70 (m, 3H),2.95 (t, J=9.9 Hz, 2H), 1.90 (d, J=10.1 Hz, 2H), 1.60-1.68 (m, 2H)

Example 21-[3-(3-Trifluoromethyl-benzenesulfonyl)-quinolin-8-yl]-pyrrolidin-3-ol

The compound was prepared in analogy to example 19 starting from8-fluoro-3-(3-(trifluoromethyl)phenylsulfonyl)quinoline andpyrrolidin-3-ol. 15 LCMS (ESI⁺) m/z [M+H]⁺: 423.10

Example 31-[3-(3-Trifluoromethyl-benzenesulfonyl)-quinolin-8-yl]-piperidine-4-carboxylicacid

8-Fluoro-3-(3-(trifluoromethyl)phenylsulfonyl)quinoline (200 mg, 0.563mmol) and piperidine-4-carboxylic acid (72.7 mg, 0.563 mmol) weresuspended in NMP (2 ml) and K₂CO₃ (233 mg, 1.689 mmol) was added andstirred at 130° C. in Microwave for 11 h.

The reaction mixture was diluted with ethyl acetate and washed 4× withwater, dried and concentrated. The residue was purified using flashchromatography (4 g column; DCM 100%→DCM:MeOH 80:20; 18 ml/min) to give1-(3-(3-(trifluoromethyl)phenylsulfonyl)quinolin-8-yl)piperidine-4-carboxylicacid (35 mg, yield 13.4%).

LCMS (ESI⁺) m/z [M+H]⁺: 465.10

¹H NMR (DMSO-d₆, 400 MHz): δ=12.18 (s, broad), 9.33 (d, J=2.4 Hz, 1H),9.14 (d, J=2.4 Hz, 1H), 8.43 (d, J=8.3 Hz, 1H), 8.40 (s, 1H), 8.12 (d,J=7.8 Hz, 1H), 7.90 (m, 1H), 7.75 (d, J=1.0 Hz, 1H), 7.64 (t, 1H), 7.36(d, J=1.2 Hz, 1H), 3.77 (d, J=12.0 Hz, 2 H), 2.87 (m, J=2.2 Hz, 2H),2.45-2.46 (m, 1H), 1.96-1.99 (m, 1H), 1.95 (br s, 1H),1.84-1.85 (m, 1H),1.82 (br. s., 1H).

Example 4(S)-1-[3-(3-Trifluoromethyl-benzenesulfonyl)-quinolin-8-yl]-piperidin-3-olhydrochloride

8-Fluoro-3-(3-(trifluoromethyl)phenylsulfonyl)quinoline (200 mg, 0.563mmol) and (S)-piperidin-3-ol hydrochloride (77 mg, 0.563 mmol) weresuspended in NMP (2 ml) and tripotassium phospate (597 mg, 2.81 mmol)was added and stirred in the Microwave at 140° C. for 11 h. The reactionmixture was diluted with ethyl acetate and washed 4× with water, driedand concentrated. The residue was purified using flash chromatography (4g column; DCM 100%→DCM:MeOH 50:50; 18 ml/min). Finally the HCl salt wasformed by adding one equivalent HCl to give(S)-1-(3-(3-(trifluoromethyl)phenylsulfonyl)quinolin-8-yl)piperidin-3-olhydrochloride (25 mg, yield 9.4%).

LCMS (ESI⁺) m/z [M+H]⁺: 437.10

¹H NMR (DMSO-d₆, 400 MHz): δ=9.35 (d, J=2.4 Hz, 1H), 9.18 (d, J=2.2 Hz,1H), 8.41-8.45 (m, 2H), 8.13-8.14 (m, 1H), 7.91 (m, 1H), 7.82 (d, J=7.6Hz, 1H), 7.67 (t, 1H), 7.46 (m, br., 1H), 3.77-3.90 (m, 3H), 2.83 (m,1H), 2.68 (m, 1H), 2.53 (m, 1H), 1.96 (br m, 1H), 1.82 (m, 1H), 1.72 (m,1H), 1.34 (m, 1H).

Example 5(R)-1-[3-(3-Trifluoromethyl-benzenesulfonyl)-quinolin-8-yl]-piperidin-3-ol

(R)-Piperidin-3-ol hydrochloride (349 mg, 2.53 mmol) and8-fluoro-3-(3-(trifluoromethyl)phenylsulfonyl)quinoline (200 mg, 0.563mmol) were suspended in NMP (2 ml) and K₂CO₃ (700 mg, 5.07 mmol) wasadded and stirred in the Microwave at 225° C. for 30 min. The reactionmixture was diluted with ethyl acetate and washed 4× with water, driedand concentrated. The residue was purified using flash chromatography(12 g column; DCM 100%→DCM:MeOH 60:40; 30 ml/min) to give(R)-1-(3-(3-(trifluoromethyl)phenylsulfonyl)quinolin-8-yl)piperidin-3-ol(140 mg, yield 57%).

LCMS (ESI⁺) m/z [M+H]⁺: 437.10

¹H NMR (DMSO-d₆, 400 MHz): δ=9.32 (d, J=2.4 Hz, 1H), 9.14 (d, J=2.2 Hz,1H), 8.43 (d, J=8.3 Hz, 1H), 8.41 (s, 1H), 8.12 (d, J=7.8 Hz, 1H), 7.91(t, J=7.8 Hz, 1H), 7.75 (dd, J=8.2, 0.9 Hz, 1H), 7.64 (t, J=7.8 Hz, 1H),7.34 (dd, J=7.7, 1.1 Hz, 1H), 4.76 (d, J=4.6 Hz, 1H), 3.73-3.83 (m, 2H),3.66 (d, J=11.5 Hz, 1H), 2.74 (d, J=2.7 Hz, 1H), 2.57 (m, 1H), 1.97 (dd,J=11.9, 3.5 Hz, 1H), 1.76-1.81 (m, 1H), 1.70 (d, J=11.5 Hz, 1H), 1.30(dd, J=9.9, 4.3 Hz, 1H).

Example 61-[3-(3-Trifluoromethyl-benzenesulfonyl)-quinolin-8-yl]-piperidine-3-carboxylicacid

8-Fluoro-3-(3-(trifluoromethyl)phenylsulfonyl)quinoline (200 mg, 0.563mmol) and piperidine-3-carboxylic acid (334 mg, 2.53 mmol) weresuspended in NMP (2 ml) and K₂CO₃ (311 mg, 2.252 mmol) was added andstirred in the Microwave at 225° C. for 35 min. The reaction mixture wasdiluted with ethyl acetate and washed 4× with water, dried andconcentrated. The residue was purified twice using flash chromatography(12 g column; DCM 100%→DCM:MeOH 60:40; 30 ml/min) to give1-(3-(3-(trifluoromethyl)phenylsulfonyl)quinolin-8-yl)piperidine-3-carboxylicacid (170 mg, yield 65%).

LCMS (ESI⁺) m/z [M+H]⁺: 465.10

¹H NMR (DMSO-d₆, 500 MHz): δ=12.35 (br s, 1H), 9.34 (d, J=2.4 Hz, I H),9.16 (d, J=2.4 Hz, 1H), 8.44 (d, J=8.2 Hz, 1H), 8.42 (s, 1H), 8.11-8.14(m, J=7.9 Hz, 1H), 7.90 (t, J=7.9 Hz, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.65(t, J=7.9 Hz, I H), 7.37-7.39 (m, J=7.3 Hz, 1H), 3.91 (d, J=9.2 Hz, 1H),3.64 (d, J=11.6 Hz, 1H), 2.85-2.93 (m, 2H), 2.68-2.73 (m, 1H), 1.99-2.05(m, 1H), 1.80-1.85 (m, 1H), 1.74 (d, J=11.3 Hz, 1H), 1.57 (dd, J=12.4,3.5 Hz, 1H).

Example 74-Methyl-1-[3-[3-(trifluoromethyl)phenyl]sulfonyl-8-quinolyl]piperidin-4-olhydrochloride

4-Methylpiperidin-4-ol (292 mg, 2.53 mmol),8-fluoro-3-(3-(trifluoromethyl)phenyl-sulfonyl)quinoline (200 mg, 0.563mmol) and K₂CO₃ (311 mg, 2.252 mmol) were suspended in NMP (2 ml) andstirred in the Microwave at 225° C. for 35 min. The reaction mixture wasdiluted with ethyl acetate and washed 4× with water, dried andconcentrated. The product was obtained by preparative HPLCchromatography on a reversed phase column. Finally the HCl salt wasformed by adding one equivalent HCl to give4-methyl-1-(3-(3-(trifluoromethyl)phenylsulfonyl)quinolin-8-yl)piperidin-4-olhydrochloride (97 mg, yield 35.4%).

LCMS (ESI⁺) m/z [M+H]⁺: 451.10

¹H NMR (DMSO-d₆, 500 MHz): δ=9.56 (d, J=2.1 Hz, 1H), 9.44 (d, J=2.1 Hz,1H), 8.43-8.53 (m, 3H), 8.32 (d, J=8.2 Hz, 1H), 8.17 (d, J=7.9 Hz, 1H),7.97 (t, J=7.9 Hz, 1H), 7.91 (t, J=7.9 Hz, 1H), 5.32-5.41 (m, broad,1H), 4.04 (br s, 2H), 3.63 (s, 1H), 3.61 (s, 1H), 2.21 (m, 2H), 1.83 (m,2H), 1.31 ppm (s, 3H).

Example 81-[3-[3-(Trifluoromethyl)phenyl]sulfonyl-8-quinolyl]azetidin-3-ol

3-Azetidinol (191 mg, 2.53 mmol) and8-fluoro-3-(3-(trifluoromethyl)phenylsulfonyl)-quinoline (200 mg, 0.563mmol) were suspended in NMP (2 ml) and K₂CO₃ (311 mg, 2.252 mmol) wasadded and stirred in the Microwave at 225° C. for 35 min. The reactionmixture was diluted with ethyl acetate and washed 4× with water, driedand concentrated. The residue was purified using flash chromatography(12 g column; DCM 100%→DCM:ethyl acetate 60:40; 30 ml/min) to give1-(3-(3-(trifluoromethyl)phenylsulfonyl)quinolin-8-yl)azetidin-3-ol (30mg, yield 13.1%).

LCMS (ESI⁺) m/z [M+H]⁺: 409.10

¹H NMR (DMSO-d₆, 500 MHz): δ=9.16 (d, J=2.4 Hz, 1H), 9.04 (d, J=2.4 Hz,I H), 8.43 (d, J=8.2 Hz, 1H), 8.40 (s, 1H), 8.13 (d, J=7.9 Hz, 1H), 7.93(s, 1H), 7.55 (m, 1 H), 7.43 (d, J=7.3 Hz, 1H), 6.73 (d, J=7.0 Hz, 1H),5.60 (d, J=6.4 Hz, 1H), 4.60 (m, 1H), 4.49-4.53 (m, 2H), 3.92 (dd,J=9.0, 4.7 Hz, 2H).

Example 9 1-[3-(3-Fluorophenyl)sulfonyl-8-quinolyl]piperidin-4-ol

8-Fluoro-3-(3-fluorophenylsulfonyl)quinoline (100 mg, 0.328 mmol) andpiperidin-4-ol (16.4 mg, 0.360 mmol) were suspended in NMP and K₂CO₃(543 mg, 3.93 mmol) was added and flushed with argon. The reactionmixture was stirred in the Microwave at 180° C. for 80 min. The reactionmixture was filtered through a fritted funnel and concentrated underhigh vacuo. The residue was dissolved in ethyl acetate and was washedwith water and brine. The organic layer was dried with sodium sulfate,filtered and concentrated. The residue was purified twice using flashchromatography (80 g column; n-heptane 100%→n-heptane:ethyl acetate0:100; 80 g column; DCM 100%→DCM:MeOH 0-100) to give1-(3-(3-fluorophenylsulfonyl)quinolin-8-yl)piperidin-4-ol (494 mg, yield46.3%).

LCMS (ESI⁺) m/z [M+H]⁺: 387.10

¹H NMR (CDCl₃, 500 MHz): δ=9.2 (s, 1H), 8.72 (s, 1H), 7.8 (d, 1H), 7.7(d, 1H), 7.45-7.6 (m, 3H), 7.2-7.35 (m, 2H), 3.95 (s, broad, 1H), 3.7(m, 2H), 3.0-3.1 (m, 2H), 2.14 (m, 2H), 1.88 (m, 2H).

Example 10 1-[3-(3-Fluorophenyl)sulfonyl-8-quinolyl]azetidin-3-ol

8-Fluoro-3-(3-fluorophenylsulfonyl)quinoline (300 mg, 0.983 mmol),azetidin-3-ol (215 mg, 2.95 mmol) and K₂CO₃ (163 mg, 1.179 mmol) weresuspended in n-propanol (5 ml) and stirred at 100° C. for 24 h. Thereaction mixture was concentrated and the residue was dissolved in DCMand water (pH 9) and acidified with 5% NH₄Cl to pH 7. The aqueous layerwas twice extracted with DCM and the combined organic layers were washedseveral times with brine, dried with sodium sulfate, filtered andconcentrated. The residue was purified using flash chromatography (40 gcolumn; n-heptane 100%→n-heptane:ethyl acetate 10:90) to give1-(3-(3-fluorophenylsulfonyl)quinolin-8-yl)azetidin-3-ol (17 mg, yield4.8%).

LCMS (ESI⁺) m/z [M+H]⁺: 359.10

¹H NMR (CDCl₃, 600 MHz): δ=9.04-9.06 (m, 1H), 8.65 (d, J=2.3 Hz, 1H),7.81 (d, J=7.9 Hz, 1H), 7.67-7.75 (m, 1H), 7.46-7.54 (m, 2H), 7.23-7.31(m, 2H), 6.67 (d, J=7.7 Hz, 1H), 4.78-4.85 (m, 1H), 4.59-4.66 (m, 2H),4.06 (dd, J=9.4, 4.5 Hz, 2H).

Example 11(3S)-1-[3-[3-(Trifluoromethyl)phenyl]sulfonyl-8-quinolyl]pyrrolidine-3-carboxylicacid

8-Fluoro-3-(3-(trifluoromethyl)phenylsulfonyl)quinoline (200 mg, 0.563mmol) and (S)-(+)-pyrrolidine-3-carboxylic acid (292 mg, 2.53 mmol) weresuspended in NMP (4 ml) and K₂CO₃ (311 mg, 2.252 mmol) was added andstirred at 225° C. in Microwave for 35 min. The reaction mixture wasdiluted with ethyl acetate and washed 4× with water, dried andconcentrated. The residue was purified using flash chromatography (12 gcolumn; DCM 100%→DCM:MeOH 60:40; 30 ml/min) to give(S)-1-(3-(3-(trifluoromethyl)phenylsulfonyl)quinolin-8-yl)pyrrolidine-3-carboxylicacid (113 mg, yield 44.6%).

LCMS (ESI⁺) m/z [M+H]⁺: 451.10

¹H NMR (DMSO-d₆, 500 MHz): δ=12.48 (br s, 1H), 9.19 (d, J=2.4 Hz, 1H),9.05 (d, J=2.4 Hz, 1H), 8.46 (d, J=8.2 Hz, 1H), 8.43 (s, 1H), 8.14 (d,J=7.9 Hz, 1H), 7.93 (t, J=7.8 Hz, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.46 (d,J=7.3 Hz, 1H), 6.94 (d, J=7.6 Hz, 1H), 3.99 (d, J=7.0 Hz, 2H), 3.67-3.72(m, 2H), 3.18 (quin, J=7.3 Hz, 1H), 2.20-2.23 (m, 1H), 2.16-2.19 (m,1H).

Example 12(3R)-1-[3-[3-(Trifluoromethyl)phenyl]sulfonyl-8-quinolyl]pyrrolidine-3-carboxylicacid

The title compound was prepared using the procedure described in example11 starting from (R)-pyrrolidine-3-carboxylic acid (64.8 mg, 0.563 mmol)and 8-fluoro-3-(3-(trifluoromethyl)phenylsulfonyl)quinoline (200 mg,0.563 mmol) to give(R)-1-(3-(3-(trifluoromethyl)phenylsulfonyl)quinolin-8-yl)pyrrolidine-3-carboxylicacid (141 mg, yield 55.6%).

LCMS (ESI⁺) m/z [M+H]⁺: 451.10

¹H NMR (DMSO-d₆, 500 MHz): δ=12.46 (s, broad, 1H), 9.18 (d, J=2.4 Hz,1H), 9.04 (d, J=2.4 Hz, 1H), 8.44 (d, J=8.2 Hz, 1H), 8.41 (s, 1H), 8.13(d, J=7.9 Hz, 1H), 7.92 (t, J=7.8 Hz, 1H), 7.53-7.55 (m, 1H), 7.45 (d,J=7.6 Hz, 1H), 6.95 (d, J=7.6 Hz, 1H), 3.98 (d, J=7.3 Hz, 2H), 3.70 (t,J=6.9 Hz, 2H), 3.17 (t, J=7.2 Hz, 1H), 2.14-2.24 (m, 2H).

Example 13 1-[3-(3-Methoxyphenyl)sulfonyl-8-quinolyl]piperidin-4-ol

Sodium sulfite (1.83 g, 14.52 mmol) was dissolved in water (16 ml) andwarmed up to 75° C. 3-Methoxybenzene-1-sulfonyl chloride (3 g, 14.52mmol) was added over 30 min. The reaction mixture was stirred at 80° C.for 7 h and at room temperature overnight and subsequently concentrated.The residue was suspended in MeOH and the precipitate was filtered andwashed with MeOH and concentrated to give sodium3-methoxybenzenesulfinate (2.7 g, yield 96%).

8-Fuoro-3-iodoquinoline (1.406 g, 5.15 mmol), sodium3-methoxybenzenesulfinate (1 g, 5.15 mmol) and copper(I)trifluoromethanesulfonate benzene complex (2.88 g, 5.15 mmol) weresuspended in DMF (20 ml) and warmed up to 65° C. for 4 h. The reactionmixture was stirred at room temperature over the weekend. The reactionmixture was filtered over a fritted funnel and concentrated. The residuewas dissolved in DCM and washed several times with 2% aqueousNH₃-solution and then several times with brine until neutral. Theorganic layer was dried with sodium sulfate, filtered and concentratedto give 8-fluoro-3-(3-methoxyphenylsulfonyl)quinoline (1.37 g, yield80%, purity 95%).

8-Fluoro-3-(3-methoxyphenylsulfonyl)quinoline (300 mg, 0.945 mmol) andpiperidin-4-ol (430 mg, 4.25 mmol) were suspended in NMP (8 ml) andK₂CO₃ (523 mg, 3.78 mmol) was added and flushed with argon. The reactionmixture was stirred in the Microwave at 225° C. for 40 min. The reactionmixture was filtered through a fritted funnel and concentrated underhigh vacuo. The residue was dissolved in ethyl acetate and 5%NH₄Cl-solution was added until pH 7 and washed several times with brine.The organic layer was dried with sodium sulfate, filtered andconcentrated. The residue was purified using flash chromatography (40 gcolumn; DCM 100%→DCM:MeOH 0:100; 40 ml/min). The crude material waspurified using Chromabond flash chromatography to give1-(3-(3-methoxyphenylsulfonyl)quinolin-8-yl)piperidin-4-ol (52 mg, yield13.1%. purity 95%).

LCMS (ESI⁺) m/z [M+H]⁺: 399.10

¹H NMR (CDCl₃, 500 MHz): δ=9.22 (m, 1H), 8.74 (m, 1H), 7.5-7.7 (m, 4H),7.41 (m, 1H), 7.26 (s, broad, 1H), 7.09 (dd, J=8.4, 2.0 Hz, 1H), 3.95(m, 1H), 3.85 (s, 3H), 3.70 (br m, 2H), 3.07 (br m, 2H), 2.13 (br m,2H), 1.91 (m, broad, 2H).

Example 14 1-[3-(3-Methoxyphenyl)sulfonyl-8-quinolyl]azetidin-3-ol

Sodium sulfite (1.83 g, 14.52 mmol) was dissolved in water (16 ml) andwarmed up to 75° C. 3-Methoxybenzene-1-sulfonyl chloride (3 g, 14.52mmol) was added over 30 min. The reaction mixture was stirred at 80° C.for 7 h and at room temperature overnight and subsequently concentrated.The residue was suspended in MeOH and the precipitate was filtered andwashed with MeOH and concentrated to give sodium3-methoxybenzenesulfinate (2.7 g, yield 96%).

8-Fluoro-3-iodoquinoline (1.406 g, 5.15 mmol), sodium3-methoxybenzenesulfinate (1 g, 5.15 mmol) and copper(I)trifluoromethanesulfonate benzene complex (2.88 g, 5.15 mmol) weresuspended in DMF (20 ml) and warmed up to 65° C. for 4 h. The reactionmixture was stirred at room temperature over the weekend. The reactionmixture was filtered over a fritted funnel and concentrated. The residuewas dissolved in DCM and washed several times with 2% aqueousNH₃-solution and then several times with brine until neutral. Theorganic layer was dried with sodium sulfate, filtered and concentratedto give 8-fluoro-3-(3-methoxyphenylsulfonyl)quinoline (1.37 g, yield80%, purity 95%).

8-Fluoro-3-(3-methoxyphenylsulfonyl)quinoline (200 mg, 0.630 mmol) andazetidin-3-ol (207 mg, 2.84 mmol) were suspended in NMP (8 ml) and K₂CO₃(348 mg, 2.52 mmol) was added and flushed with argon. The reactionmixture was stirred in the Microwave at 225° C. for 40 min andsubsequently concentrated under high-vacuum. The residue was dissolvedin ethyl acetate and washed with water and brine. The organic layer wasdried with sodium sulfate, filtered and concentrated. The residue waspurified using flash chromatography (40 g column). The crude materialwas purified twice using Chromabond flash chromatography to give1-(3-(3-methoxyphenylsulfonyl)quinolin-8-yl)azetidin-3-ol (76.8 mg,yield 31.3%, purity 95%).

LCMS (ESI⁺) m/z [M+H]⁺: 371.10

¹H NMR (CDCl₃, 500 MHz): δ=9.04 (d, J=2.4 Hz, 1H), 8.64 (d, J=2.1 Hz,1H), 7.57 (d, J=7.9 Hz, 1H), 7.50-7.51 (m, 1H), 7.48 (s, 1H), 7.42 (s,1H), 7.26 (s, 1H), 7.09 (dd, J=8.2, 1.8 Hz, 1H), 6.65 (s, 1H), 4.62 (m,1H), 4.06 (m, 1H), 3.85 (s, 3H), 1.59 (br s, 1H), 1.25 (s, 1H).

Example 151-[3-(3-Methoxyphenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylic acid

Sodium sulfite (1.83 g, 14.52 mmol) was dissolved in water (16 ml) andwarmed up to 75° C. 3-Methoxybenzene-1-sulfonyl chloride (3 g, 14.52mmol) was added over 30 min. The reaction mixture was stirred at 80° C.for 7 h and at room temperature overnight and subsequently concentrated.The residue was suspended in MeOH and the precipitate was filtered andwashed with MeOH and concentrated to give sodium3-methoxybenzenesulfinate (2.7 g, yield 96%).

8-Fluoro-3-iodoquinoline (1.406 g, 5.15 mmol), sodium3-methoxybenzenesulfinate (1 g, 5.15 mmol) and copper(I)trifluoromethanesulfonate benzene complex (2.88 g, 5.15 mmol) weresuspended in DMF (20 ml) and warmed up to 65° C. for 4 h. The reactionmixture was stirred at room temperature over the weekend. The reactionmixture was filtered over a fritted funnel and concentrated. The residuewas dissolved in DCM and washed several times with 2% aqueousNH₃-solution and then several times with brine until neutral. Theorganic layer was dried with sodium sulfate, filtered and concentratedto give 8-fluoro-3-(3-methoxyphenylsulfonyl)quinoline (1.37 g, yield80%, purity 95%).

The title compound was prepared using the procedure described in example15 starting from 8-fluoro-3-(3-methoxyphenylsulfonyl)quinoline (200 mg,0.630 mmol) and piperidine-4-carboxylic acid (366 mg, 2.84 mmol) to give1-(3-(3-methoxyphenylsulfonyl)quinolin-8-yl)piperidine-4-carboxylic acid(14.6 mg, yield 5.2%, purity 95%).

LCMS (ESI⁺) m/z [M+H]⁺: 427.10

Example 161-[3-[[8-(4-Hydroxy-1-piperidyl)-3-quinolyl]sulfonyl]phenyl]piperidin-4-ol

8-Fluoro-3-iodoquinoline (4 g, 14.65 mmol), sodium3-fluorobenzenesulfinate (4.8 g, 26.4 mmol) and copper(I)trifluoromethanesulfonate benzene complex (8.19 g, 14.65 mmol) weresuspended in DMF (80 ml) and warmed up to 65° C. for 4 h. The reactionmixture was stirred at room temperature over the weekend. The reactionmixture was filtered over a fritted funnel and concentrated. The residuewas dissolved in DCM and washed several times with 2% aqueousNH₃-solution and then several times with brine until neutral. Theorganic layer was dried with sodium sulfate, filtered and concentrated.The residue was purified using flash chromatography (120 g column; DCM100%→DCM:MeOH 85:15). The crude material was purified using Chromabondflash chromatography to give8-fluoro-3-(3-fluorophenylsulfonyl)quinoline (1.4 g, yield 29.7%).

8-fluoro-3-(3-fluorophenylsulfonyl)quinoline (600 mg, 1.966 mmol) andpiperidin-4-ol (894 mg, 8.84 mmol) were suspended in NMP (16 ml) andK₂CO₃ (1.086 g, 7.86 mmol) was added and flushed with argon. Thereaction mixture was stirred in the Microwave at 225° C. for 40 min andsubsequently concentrated under high-vacuum. The residue was purifiedusing flash chromatography (80 g column; DCM 100%→DCM:MeOH 90:10) togive1-(3-(3-(4-hydroxypiperidin-1-yl)phenylsulfonyl)quinolin-8-yl)piperidin-4-ol(122 mg, yield 13.3%).

LCMS (ESI⁺) m/z [M+H]⁺: 468.20

¹H NMR (CDCl₃, 500 MHz): δ=9.22 (br s, 1H), 8.73 (br s, 1H), 7.5-7.65(m, 3H), 7.29-7.39 (m, 3H), 7.07 (d, J=7.0 Hz, 1H), 3.85-4.0 (br m, 2H),3.71 (br m, 2H), 3.57-3.63 (in, broad, 2H), 2.99-3.09 (m, broad, 2H),2.13 (br. m., 2H), 1.96-2.04 (m, 2H), 1.92 (br m, 2H), 1.64-1.71 (m,2H), 1.49 (br m, 2H).

Example 171-[3-[[8-(4-Carboxy-1-piperidyl)-3-quinolyl]sulfonyl]phenyl]piperidine-4-carboxylicacid

8-Fluoro-3-(3-fluorophenylsulfonyl)quinoline (200 mg, 0.655 mmol) andpiperidine-4-carboxylic acid (381 mg, 2.95 mmol) were suspended in NMP(8 ml) and K₂CO₃ (362 mg, 2.62 mmol) was added and flushed with argon.The reaction mixture was stirred in the Microwave at 225° C. for 40 minand subsequently concentrated under high-vacuum. The residue wasdissolved in ethyl acetate and washed with water. The aqueous layer wasacidified with 1M HCl to pH 4 and extracted several times with ethylacetate. The combined organic layers were washed with brine, dried withsodium sulfate, filtered and concentrated. The residue was purifiedusing flash chromatography (40 g column). The crude material waspurified using Chromabond flash chromatography to give1-(3-(3-(4-carboxypiperidin-1-yl)phenylsulfonyl)quinolin-8-yl)piperidine-4-carboxylicacid (9.8 mg, yield 2.7%).

LCMS (ESI⁺) m/z [M+H]⁺: 524.20

¹H NMR (DMSO-d₆, 500 MHz): δ=12.23 (br s, 2H), 9.25 (s, 1H), 9.04 (s,1H), 7.75 (d, J−7.9 Hz, 1H), 7.62 (t, J=7.6 Hz, 1H), 7.50 (s, 1H), 7.42(d, J=8.2 Hz, 1H), 7.38-7.40 (m, 1H), 7.33 (d, J=7.6 Hz, 1H), 7.25 (d,J=8.5 Hz, 1H), 3.75 (d, J=11.3 Hz, 4H), 2.85 (t, J=11.7 Hz, 4H), 2.44(d, J=7.0 Hz, 2H), 1.88-1.98 (m, 4H), 1.83 (d, J=11.0 Hz, 2H), 1.61 (d,J=10.7 Hz, 2H).

Example 18 1-[3-(Benzenesulfonyl)-8-quinolyl]piperidin-4-ol

Sodium hydrogencarbonate (3.81 g, 45.3 mmol) and sodium sulfite (2.85 g,22.65 mmol) were dissolved in water (20 ml) and warmed up to 75° C.Benzenesulfonyl chloride (2.89 ml, 22.65 mmol) was added in 30 min andstirred at 80° C. for 7 h and at room temperature over the weekend. Thereaction mixture was concentrated and dissolved in MeOH (20 ml),stirred, filtered and concentrated to give sodium benzenesulfinate (4.1g, yield 99%, purity 90%).

8-Fluoro-3-iodoquinoline (2.99 g, 10.97 mmol), sodium benzenesulfinate(2 g, 10.97 mmol) and copper(I) trifluoromethanesulfonate benzenecomplex (5.52 g, 10.97 mmol) were dissolved in DMF (40 ml) and warmed upto 65° C. and stirred for 6 h. The reaction mixture stirred at roomtemperature overnight. The reaction mixture was filtered over a frittedfunnel and concentrated. The residue was dissolved in DCM and washed 3×with NH₄OH-solution. The organic layer was dried, filtered andconcentrated to give 8-fluoro-3-(phenylsulfonyl)quinoline (3.4 g, yield97%, purity 90%).

The title compound was prepared using the procedure described in example14 starting from piperidin-4-ol (562 mg, 5.56 mmol) and8-fluoro-3-(phenylsulfonyl)quinoline (355 mg, 1.236 mmol) to give1-(3-(phenylsulfonyl)quinolin-8-yl)piperidin-4-ol (188 mg, yield 41.3%).

LCMS (ESI⁺) m/z [M+H]⁺: 369.10

¹H NMR (CDCl₃, 500 MHz): δ=9.23 (br s, 1H), 8.76 (br s, 1H), 8.02 (d,J=7.9 Hz, 2H), 7.51-7.59 (m, 5H), 3.94 (m, broad, 1H), 3.71 (br m, 2H),3.08 (br m, 2H), 2.14 (br m, 2H), 1.92 (br m, 2H).

Example 19(3R)-1-[3-[3-(Trifluoromethyl)phenyl]sulfonyl-8-quinolyl]pyrrolidin-3-ol

The title compound was prepared using the procedure described in example11 starting from 8-fluoro-3-(3-(trifluoromethyl)phenylsulfonyl)quinoline(150 mg, 0.422 mmol) and (R)-pyrrolidin-3-ol (166 mg, 1.900 mmol) togive(R)-1-(3-(3-(trifluoromethyl)phenylsulfonyl)quinolin-8-yl)pyrrolidin-3-ol(31 mg, yield 17.4%).

LCMS (ESI⁺) m/z [M+H]⁺: 423.10

¹H NMR (CDCl₃, 500 MHz): δ=9.06 (d, J=2.1 Hz, 1H), 8.68 (d, J=2.1 Hz,1H), 8.29 (s, 1H), 8.19-8.22 (m, J=7.9 Hz, 1H), 7.84 (d, J=7.9 Hz, 1H),7.67-7.71 (m, 1H), 7.50 (t, J=7.9 Hz, 1H), 7.25-7.28 (m, 1H), 6.91-6.94(m, J=7.6 Hz, 1H), 4.62 (br s, 1H), 4.14 (dd, J=11.9, 4.6 Hz, 1H),3.92-3.98 (m, 1H), 3.78 (d, J=1 1.9 Hz, 1H), 3.64-3.69 (m, 1H), 2.19 (m,1H), 2.09 (m, 1H).

Example 20 (3R)-1-[3-(3-Fluorophenyl)sulfonyl-8-quinolyl]piperidin-3-ol

2,2-Bis(diphenylphosphino)-1,1-binaphtyl (BINAP) (15.07 mg, 0.024 mmol),tris(dibenzylideneacetone)dipalladium(0) (11.08 mg, 0.012 mmol), cesiumcarbonate (867 mg, 2.66 mmol) and (R)-piperidin-3-ol (171 mg, 1,694mmol) were added and flushed with argon overnight. Then degassed toluene(10 ml) was added and stirred at 50° C. for 10 min. Finally3-(3-fluorophenylsulfonyl)-8-iodoquinoline (500 mg, 1.210 mmol) wasadded and stirred at 100° C. overnight. The reaction mixture wasconcentrated. The residue was dissolved in DCM and water and the aqueouslayer was acidified with 0.1M HCl (pH 7). The organic layer was washedseveral times with water and finally with brine, dried with sodiumsulfate, filtered and concentrated. The residue was purified using flashchromatography (40 g column; DCM 100%→DCM:MeOH 90:10) to give(R)-1-(3-(3-fluorophenylsulfonyl)quinolin-8-yl)piperidin-3-ol (170 mg,yield 34.5%, purity 95%).

LCMS (ESI⁺) m/z [M+H]⁺: 387.10

¹H NMR (CDCl₃, 600 MHz): δ=9.18 (d, J=1.9 Hz, 1H), 8.76-8.79 (m, 1H),7.83 (d, J=7.9 Hz, 1H), 7.72 (d, J=7.7 Hz, 1H), 7.51-7.60 (m, 3H),7.2-7.35 (several m, 2H), 4.13-4.17 (m, very broad, 1H), 4.09 (br s,1H), 3.69 (m, 1H), 3.32 (m, 1H), 3.22 (m, 1H), 3.14 (m, 1H), 2.15 (m,1H), 1.87-1.93 (m, 1H), 1.68-1.76 (m, 2H).

Example 21 1-[3-(2-Methoxyphenyl)sulfonyl-8-quinolyl]piperidin-4-ol

The title compound was prepared using the procedure described in example13 starting from 8-fluoro-3-(2-methoxyphenylsulfonyl)quinoline (400 mg,1.260 mmol) and piperidin-4-ol (574 mg, 5.67 mmol) to give1-(3-(2-methoxyphenylsulfonyl)quinolin-8-yl)piperidin-4-ol (22.4 mg,yield 4.2%, purity 95%).

LCMS (ESI⁺) m/z [M+H]⁺: 399.10

¹H NMR (CDCl₃, 600 MHz): δ=9.22 (br s, 1H), 8.80 (br s, 1H), 8.22-8.25(m, J=7.7 Hz, 1H), 7.52-7.60 (m, 3H), 7.30 (br s, 1H), 7.15 (t, J=7.6Hz, 1H), 6.87-6.91 (m, J=8.3 Hz, 1H), 3.95 (br s, 1H), 3.75 (s, 4H),3.08 (br s, 2H), 2.12-2.18 (m, 2H), 1.92 (m, 2H), 1.49 (br m, 1H).

Example 22 (3S)-1-[3-(Benzenesulfonyl)-8-quinolyl]piperidin-3-ol

The title compound was prepared using the procedure described in example18 to give (S)-1-(3-(phenylsulfonyl)quinolin-8-yl)piperidin-3-ol (220mg, yield 54.3%, purity 95%).

LCMS (ESI⁺) m/z [M+H]⁺: 369.10

¹H NMR (CDCl₃, 600 MHz): δ=9.18 (s, 1H), 8.78 (s, 1H), 8.03 (m, 2H),7.59-7.62 (m, 1H), 7.5-7.6 (m, 4H), 7.25 (m, 1H), 4.21 (br s, 1H), 4.08(br m, 1H), 3.69 (m, 1H), 3.32 (m, 1H), 3.21 (m, 1H), 3.13 (m, 1H), 2.15(m, 1H), 1.87-1.93 (m, 1H), 1.67-1.75 (m, 2H).

Example 23 (3R)-1-[3-(Benzenesulfonyl)-8-quinolyl]piperidin-3-ol

The title compound was prepared using the procedure described in example18 to give (R)-1-(3-(phenylsulfonyl)quinolin-8-yl)piperidin-3-ol (163mg, yield 42.4%).

LCMS (ESI⁺) m/z [M+H]⁺: 369.10

¹H NMR (CDCl₃, 600 MHz): δ=9.18 (s, 1H), 8.78 (s, 1H), 8.03 (m, 2H),7.59-7.62 (m, 1H), 7.54 (m, 4H), 7.26 (m, 1H), 4.21 (br s, 1H), 4.08 (brm, 1H), 3.69 (m, 1H), 3.32 (m, 1H), 3.21 (m, 1H), 3.13 (m, 1H), 2.15 (m,1H), 1.87-1.94 (m, 1H), 1.67-1.75 (m, 2H).

Example 24 1-[3-[(8-Fluoro-3-quinolyl)sulfonyl]phenyl]piperidin-4-ol

8-Fluoro-3-(3-fluorophenylsulfonyl)quinoline (100 mg, 0.328 mmol) andpiperidin-4-ol (16.4 mg, 0.360 mmol) were suspended in NMP (25 ml) andK₂CO₃ (543 mg, 3.93 mmol) was added and flushed with argon. The reactionmixture was stirred at 180° C. for 80 min and then filtered over afritted funnel and concentrated under high-vacuum. The residue wasdissolved in ethyl acetate and washed with water and brine. The organiclayer was dried with sodium sulfate, filtered and concentrated. Theresidue was purified twice using flash chromatography (80 g column; DCM100%→DCM:MeOH 0:100; 80 g column; cyclohexane 100%→cyclohexane:ethylacetate 0-100). The crude product was purified using Chromabond flashchromatography to give1-(3-(8-fluoroquinolin-3-ylsulfonyl)phenyl)piperidin-4-ol (28 mg, yield2.5%, purity 92%).

LCMS (ESI⁺) m/z [M+H]⁺: 387.10

¹H NMR (CDCl₃, 600 MHz): δ=9.32 (d, J=1.7 Hz, 1H), 8.83 (s, 1H), 7.78(d, J=8.3 Hz, 1H), 7.64 (m, 1H), 7.51-7.59 (m, 2H), 7.38 (m, 2H), 7.26(s, 8H), 7.12 (br m, 1H), 3.92 (br m, 1H), 3.60-3.64 (m, 2H), 3.05 (m,2H), 2.02 (br m, 2H), 1.66-1.71 (m, 2H).

Example 25 1-[2-[(8-Fluoro-3-quinolyl)sulfonyl]phenyl]piperidin-4-ol

The title compound was prepared using the procedure described in example25 starting with 8-fluoro-3-(2-fluorophenylsulfonyl)quinoline (500 mg,1.638 mmol) and piperidin-4-ol (182 mg, 1.802 mmol) to give1-(2-(8-fluoroquinolin-3-ylsulfonyl)phenyl)-piperidin-4-ol (238 mg,yield 37.6%).

LCMS (ESI⁺) m/z [M+H]⁺: 387.10

¹H NMR (DMSO-d₆, 600 MHz): δ=9.28 (d, J=1.9 Hz, 1H), 9.03 (s, 1H), 8.26(d, J=7.9 Hz, 1H), 8.10 (d, J=8.1 Hz, 1H), 7.79-7.83 (m, 1H), 7.75-7.79(m, 2H), 7.54 (t, J=7.6 Hz, 1H), 7.49 (d, J=7.9 Hz, 1H), 4.66 (br s,1H), 3.51 (br s, 1H), 2.66 (br m, 2H), 2.49-2.57 (m, 1H), 1.58 (d, J=9.8Hz, 2H), 1.27-1.35 (m, 2H).

Example 26 (3S)-1-[3-(3-Fluorophenyl)sulfonyl-8-quinolyl]pyrrolidin-3-ol

2,2-Bis(diphenylphosphino)-1,1-binaphtyl (BINAP) (7.53 mg, 0.012 mmol),tris(dibenzylideneacetone)dipalladium(0) (11.08 mg, 0.012 mmol), cesiumcarbonate (867 mg, 2.66 mmol) and3-(3-fluorophenylsulfonyl)-8-iodoquinoline (500 mg, 1.210 mmol), wereadded and flushed with argon for 6 h. Then degassed toluene (10 ml) wasadded and stirred at 50° C. for 10 min. Finally3-(3-fluorophenylsulfonyl)-8-iodoquinoline (105 mg, 1.210 mmol) wasadded and stirred at 100° C. over the weekend. The reaction mixture wasconcentrated. The residue was dissolved in DCM and water. The aqueouslayer was washed twice with DCM. The combined organic layers were washedwith brine, dried with sodium sulfate, filtered and concentrated. Theresidue was purified twice using flash chromatography (24 g column; DCM100%→DCM:MeOH 90:10) to give(S)-1-(3-(3-fluorophenylsulfonyl)quinolin-8-yl)pyrrolidin-3-ol (148 mg,yield 31.2%, purity 95%).

LCMS (ESI⁺) m/z [M+H]⁺: 373.10

¹H NMR (CDCl₃, 500 MHz): δ=9.02 (s, 1H), 8.57 (s, 1H), 7.9 (d, 1H), 7.7(1, 1H), 7.45-7.6 (m, 2H), 7.2-7.3 (m, 2H), 6.9 (m, broad, 1H), 4.6 (m,broad, 1H), 4.1 (m, 1H), 3.95 (m, 1H), 3.75 (m, 1H), 3.65 (m, 1H), 2.7(m, 1H), 2.6 (m, 1H).

Example 27 (3S)-1-[3-(3-Fluorophenyl)sulfonyl-8-quinolyl]piperidin-3-ol

The title compound was prepared using the procedure described in example20 starting from 3-(3-fluorophenylsulfonyl)-8-iodoquinoline (500 mg,1.210 mmol) and (S)-piperidin-3-ol (171 mg, 1.694 mmol) to give(S)-1-(3-(3-fluorophenylsulfonyl)quinolin-8-yl)piperidin-3-ol (32.5 mg,yield 6.4%, purity 92%).

LCMS (ESI⁺) m/z [M+H]⁺: 387.10

¹H NMR (CDCl₃, 600 MHz): δ=9.20 (br s, 1H), 8.79 (br s, 1H), 7.83 (d,J=7.7 Hz, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.60 (br s, 1H), 7.52-7.58 (m,2H), 7.31 (t, J=7.7 Hz, 1H), 7.26 (m, 1H), 4.11 (br s, 1H), 3.69 (br s,1H), 3.0-3.45 (m, broad, 3H), 2.17 (m, broad, 1H), 1.91 (br s, 1H), 1.74(br s, 2H).

Example 281-[3-(2-Hydroxy-5-methyl-phenyl)sulfonyl-8-quinolyl]piperidin-4-ol

The title compound was prepared using the procedure described in example14 starting from 8-fluoro-3-(2-methoxy-5-methylphenylsulfonyl)quinoline(400 mg, 1.207 mmol), piperidin-4-ol (549 mg, 5.43 mmol) to give1-(3-(2-hydroxy-5-methylphenylsulfonyl)-quinolin-8-yl)piperidin-4-ol(62.5 mg, yield 12.3%, purity 95%).

LCMS (ESI⁺) m/z [M+H]⁺: 399.10

¹H NMR (DMSO-d₆, 600 MHz): δ=10.70 (br s, 1H), 9.13-9.15 (s, 1H), 8.93(s, 1H), 7.80 (s, 1H), 7.75 (d, J=8.1 Hz, 1H), 7.59 (t, J=7.9 Hz, 1H),7.32 (m, 2H), 6.77 (d, J=7.9 Hz, 1H), 4.70-4.73 (m, 1H), 3.63-3.71 (m,3H), 2.94 (m, 2H), 2.31 (s, 3H), 1.91 (d, J=10.4 Hz, 2H), 1.65 (q, J=9.1Hz, 2H).

Example 291-[3-[3-(Difluoromethoxy)phenyl]sulfonyl-8-quinolyl]piperidin-4-ol

Sodium hydrogencarbonate (1.385 g, 16.49 mmol) and sodium sulfite (1.039g, 8.24 mmol) were dissolved in water (10 ml) and warmed up to 75° C.for 30 min. 3-(Difluoromethoxy)benzene-1-sulfonyl chloride (2 g, 8.24mmol) was added dropwise in 30 min and warmed up to 80° C. for 6 h. Thereaction mixture was stirred at room temperature overnight. The reactionmixture was concentrated and dried under high-vacuum. The residue wassuspended twice in MeOH (10 ml) and stirred for 10 min. The solid wasfiltered. The filtrates were combined and concentrated to give sodium3-(difluoromethoxy)benzenesulfinate (1.206 g, yield 63.6%).

8-Fluoro-3-iodoquinoline (1.431 g, 5.24 mmol),copper(I)trifluoromethanesulfonate benzene complex (2.64 g, 5.24 mmol)and sodium 3-(difluoromethoxy)benzenesulfinate (1.206 g, 5.24 mmol) weresuspended in DMF (20 ml) and warmed up to 65° C. for 6 h. The reactionmixture was stirred at room temperature over the weekend. The reactionmixture was filtered over a fritted funnel and washed with DCM. Thefiltrates were combined and concentrated. The residue was purified usingflash chromatography (40 g column; DCM 100%→DCM:MeOH 20:80). One part ofthe product crystallized over 3 weeks. These crystals were filtered andwashed with MeOH and dried under vacuum. The filtrate was concentratedand twice purified using flash chromatography to give3-(3-(difluoromethoxy)phenylsulfonyl)-8-fluoroquinoline (1.83 g, yield99%). 3-(3-(Difluoromethoxy)phenylsulfonyl)-8-fluoroquinoline (270 mg,0.764 mmol), piperidin-4-ol (348 mg, 3.44 mmol) and cesium carbonate(996 mg, 3.06 mmol) were suspended in NMP (5 ml) and flushed with argonand stirred at 210° C. for 30 min. Silica gel was added and purifiedusing flash chromatography (80 g column; DCM 100%→DCM:MeOH 20:80). Thecrude product was dissolved in ethyl acetate and washed 3× with water.The organic layer was dried and concentrated and purified by preparativeHPLC chromatography on a reversed phase column to give1-(3-(3-(difluoromethoxy)-phenylsulfonyl)quinolin-8-yl)piperidin-4-ol(24 mg, yield 7.2%)

LCMS (ESI⁺) m/z [M+H]⁺: 435.10

¹H NMR (CDCl₃, 600 MHz): δ=9.33-9.35 (m, 1H), 8.91-8.94 (m, 1H), 8.08(d, J=8.1 Hz, 1H), 7.89 (d, J=7.3 Hz, 1H), 7.80 (br m, 2H), 7.77 (br m,1H), 7.59 (m, 1H), 7.41 (m, 1H), 6.59 (t, 1H), 4.47 (br s, 2H), 4.30 (brm, 1H), 3.80 (br m, 2H), 2.62 (br m, 2H), 2.15 (br m, 2H).

Example 30 (3S)-1-[3-(Benzenesulfonyl)-8-quinolyl]pyrrolidin-3-ol

The title compound was prepared using the procedure described in example6 starting from 8-fluoro-3-(phenylsulfonyl)quinoline (300 mg, 1.044nmol) and (S)-(−)-3-pyrrolidinol (409 mg, 4.70 mmol) to give(S)-1-(3-(phenylsulfonyl)quinolin-8-yl)pyrrolidin-3-ol (150 mg, yield38.1%, purity 94%).

LCMS (ESI⁺) m/z [M+H]⁺: 355.10

¹H NMR (CDCl₃, 600 MHz): δ=9.07 (br s, 1H), 8.67 (br s, 1H), 8.02 (m,2H), 7.59 (m, 1H), 7.47-7.56 (m, 3H), 7.26 (m, 1H), 6.92 (br s, 1H),4.62 (br m, 1H), 4.13 (br m, 1H), 3.92-3.99 (m, 1H), 3.77 (m, 1H), 3.66(br m, 1H), 2.21 (br m, 1H), 2.10 (br m, 1H).

Example 311-[3-[3-(Difluoromethoxy)phenyl]sulfonyl-8-quinolyl]piperidine-4-carboxylicacid

The title compound was prepared using the procedure described in example29 to give1-(3-(3-(difluoromethoxy)phenylsulfonyl)quinolin-8-yl)piperidine-4-carboxylicacid (52.2 mg, yield 14.8%).

LCMS (ESI⁺) m/z [M+H]⁺: 463.10

¹H NMR (DMSO-d₆, 600 MHz): δ=12.26 (br s, 1H), 9.29 (br s, 1H), 9.10 (brs, 1H), 7.98 (m, 1H), 7.88 (br s, 1H), 7.77 (m, 1H), 7.72 (m, 1H), 7.64(m, 1H), 7.54 (m, 1H), 7.41 (t, 1H), 7.35 (m, 1H), 3.77 (m, 2H), 2.86(m, 2H), 2.45 (m, 1H), 1.96 (m, 2H), 1.82 (m, 2H).

Example 32(3S,4S)-1-[3-(Benzenesulfonyl)-8-quinolyl]pyrrolidine-3,4-diol

2,2-Bis(diphenylphosphino)-1,1-binaphtyl (BINAP) (6.30 mg, 10.12 mmol),tris(dibenzylideneacetone)dipalladium(0) (9.27 mg, 10.12 μmol), cesiumcarbonate (725 mg, 2.227 mmol) and 8-iodo-3-(phenylsulfonyl)quinoline(400 mg, 1.012 mmol), were added and flushed with argon for 3 h. Thentrans-3,4-dihydroxypyrrolidin (104 mg, 1.012 mmol) was dissolved indegassed DMF (5 ml) and added to the reaction mixture. The reactionmixture was stirred at 100° C. over the weekend and subsequentlyfiltered over a fritted funnel and concentrated under high-vacuum. Theresidue was dissolved in ethyl acetate and acidified with 5%NH₄Cl-solution to pH 7, washed with water and several times with brine.The organic layer was dried with sodium sulfate, filtered andconcentrated. The residue was purified using flash chromatography (12 gcolumn; DCM 100%→DCM:MeOH 80:20). The crude product was purified usingChromabond flash chromatography to givetrans-1-(3-(phenylsulfonyl)quinolin-8-yl)pyrrolidine-3,4-diol (9.8 mg,yield 2.6%).

LCMS (ESI⁺) m/z [M+H]⁺: 371.10

¹H NMR (CDCl₃, 600 MHz): δ=9.07 (s, 1H), 8.70 (s., 1H), 7.97-8.05 (m,2H), 7.5-7.7 (several m, 5H), 7.36 (br s, 1H), 4.37 (br m, 2H),4.23-4.26 (m, 2H), 3.72 (in, 2H).

Example 33 (3R)-1-[3-(3-Fluorophenyl)sulfonyl-8-quinolyl]pyrrolidin-3-ol

The title compound was prepared using the procedure described in example26 starting from 3-(3-fluorophenylsulfonyl)-8-iodoquinoline (200 mg,0.484 mmol) and (R)-pyrrolidin-3-ol (42.2 mg, 0.484 mmol) to give(R)-1-(3-(3-fluorophenylsulfonyl)-quinolin-8-yl)pyrrolidin-3-ol (9.1 mg,yield 4.7%, purity 93%).

LCMS (ESI⁺) m/z [M+H]⁺: 373.10

¹H NMR (CDCl₃, 600 MHz): δ=9.05 (s, 1H), 8.66 (br s, 1H), 7.81 (m, 1H),7.72 (m, 1H), 7.48-7.56 (m, 2H), 7.23-7.31 (m, 2H), 6.94 (br s, 1H),4.62 (br m, 1H), 4.09-4.17 (m, 1H), 3.92-3.99 (m, 1H), 3.77 (m, 1H),3.66 (br m, 1H), 2.24-2.27 (m, 1H), 2.09 (m, 1H).

Example 34 (3R,4R)-1-[3-(Benzenesulfonyl)-8-quinolyl]piperidine-3,4-diol

The title compound was prepared using the procedure described in example32 starting 30 from 8-iodo-3-(phenylsulfonyl)quinoline (400 mg, 1,012mmol) and (3S,4S)-pyrrolidine-3,4-diol (110 mg, 1,012 mmol) to give(3R,4R)-1-(3-(phenylsulfonyl)quinolin-8-yl)piperidine-3,4-diol (42 mg,yield 10.8%).

LCMS (ESI⁺) m/z [M+H]⁺: 385.10

Example 351-[3-(2-Methoxy-5-methyl-phenyl)sulfonyl-8-quinolyl]piperidin-4-ol

8-Fluoro-3-(2-methoxy-5-methylphenylsulfonyl)quinoline (200 mg, 0.604mmol), piperidin-4-ol (61 mg, 0.604 mmol) and K₂CO₃ (100 mg, 0.724 mmol)were suspended in n-propanol and stirred at 100° C. for 24 h. Thereaction mixture was concentrated and dissolved in DCM and water. Theaqueous layer was twice washed with DCM. The organic layer was acidifiedwith 5% NH₄Cl-solution (pH 7), washed with brine, dried with sodiumsulfate, filtered and concentrated. The residue was purified twice usingflash chromatography (12 g column; n-heptane 100%→n-heptane:ethylacetate 0:100) to give1-(3-(2-methoxy-5-methylphenylsulfonyl)quinolin-8-yl)piperidin-4-ol(10.5 mg, yield 4%, purity 95%).

LCMS (ESI⁺) m/z [M+H]⁺: 413.10

¹H NMR (CDCl₃, 600 MHz): δ=9.22 (s, 1H), 8.79 (s, 1H), 8.02 (s, 1H),7.54 (m, 2H), 7.35 (m, 1H), 7.24-7.32 (m, 1H), 6.78 (m, 1H), 3.95 (br m,1H), 3.71 (m, 2H), 3.71 (s, 3H), 3.07 (br m, 2H), 2.39 (s, 3H),2.11-2.20 (m, 2H), 1.92 (m, 2H), 1.26 (m, 1H).

Example 36 (3R,5S)-1-[3-(Benzenesulfonyl)-8-quinolyl]piperidine-3,5-diol

The title compound was prepared using the procedure described in example32 starting from 8-iodo-3-(phenylsulfonyl)quinoline (400 mg, 1.012 mmol)and (3S,4S)-pyrrolidine-3,4-diol (110 mg, 1.012 mmol) to give(3R,5S)-1-(3-(phenylsulfonyl)quinolin-8-yl)piperidine-3,5-diol (33.5 mg,yield 8.2%, purity 95%).

LCMS (ESI⁺) m/z [M+H]⁺: 385.10

¹H NMR (CDCl₃, 600 MHz): δ=9.12 (s, 1H), 8.81 (s, 1H), 8.04 (m, 2H),7.5-7.65 (several m, 5H), 7.29 (m, 1H), 4.16 (m, 2H), 3.94 (m, 2H), 3.23(m, 2H), 2.37 (m, 1H), 1.76 (m, 1H).

Example 37 1-[3-(Benzenesulfonyl)-8-quinolyl]piperidine-4-carboxylicacid

The title compound was prepared using the procedure described in example14 starting from piperidine-4-carboxylic acid (607 mg, 4.70 mmol) and8-fluoro-3-(phenylsulfonyl)quinoline (300 mg, 1.044 mmol). The productwas obtained by preparative HPLC chromatography on a reversed phasecolumn to give1-(3-(phenylsulfonyl)quinolin-8-yl)piperidine-4-carboxylic acid (84 mg,yield 20.3%).

LCMS (ESI⁺) m/z [M+H]⁺: 397.10

¹H NMR (DMSO-d₆, 600 MHz): δ=9.23 (br s, 1H), 9.04 (br s, 1H), 8.10 (m,2H), 7.5-7.8 (several m, 5H), 7.31 (br m, 1H), 3.73 (br m, 2H), 2.84 (m,2H), 2.31 (br m, 1H), 1.89-1.95 (m, 2H), 1.78-1.86 (m, 2H).

Example 38 1-[2-[(8-Fluoro-3-quinolyl)sulfonyl]phenyl]azetidin-3-ol

The title compound was prepared using the procedure described in example35 starting from 8-fluoro-3-(2-fluorophenylsulfonyl)quinoline (300 mg,0.983 mmol) and azetidin-3-ol (215 mg, 2.95 mmol) to give1-(2-(8-fluoroquinolin-3-ylsulfonyl)phenyl)azetidin-3-ol (64 mg, yield18.2%).

LCMS (ESI⁺) m/z [M+H]⁺: 359.05

¹H NMR (CDCl₃, 500 MHz): δ=9.26 (s, 1H), 8.73 (s, 1H), 7.99 (d, J=7.9Hz, 1H), 7.76 (d, J=8.2 Hz, 1H), 7.61-7.66 (m, 1H), 7.55-7.60 (m, 1H),7.48 (t, J=7.8 Hz, 1H), 6.98 (t, J=7.6 Hz, 1H), 6.72 (d, J=8.2 Hz, 1H),4.61 (m, 1H), 4.28 (m, 2H), 3.82 (m, 2H), 2.11 (m, 1H).

Example 39 1-[3-(2-Methoxyphenyl)sulfonyl-8-quinolyl]azetidin-3-ol

The title compound was prepared using the procedure described in example35 starting from 8-fluoro-3-(2-methoxyphenylsulfonyl)quinoline (200 mg,0.630 mmol) and azetidin-3-ol (138 mg, 1.891 mmol to give1-(3-(2-methoxyphenylsulfonyl)quinolin-8-yl)azetidin-3-ol (21 mg, yield8.4%, purity 93%).

LCMS (ESI⁺) m/z [M+H]⁺: 371.10

¹H NMR (CDCl₃, 600 MHz): δ=9.08 (s, 1H), 8.68 (s, 1H), 8.21 (d, 1H),7.52-7.60 (m, 1H), 7.45 (t, J=7.9 Hz, 1H), 7.20-7.28 (m, 1H), 7.14 (t,J=7.6 Hz, 1H), 6.89 (d, J=8.3 Hz, 1H), 6.67 (d, J=7.5 Hz, 1H), 4.81 (m,1H), 4.66-4.72 (m, 2H), 4.06 (m, 2H), 3.76 (s, 3H), 3.76 (m, 1H).

Example 401-[3-(2-Methoxy-5-methyl-phenyl)sulfonyl-8-quinolyl]azetidin-3-ol

The title compound was prepared using the procedure described in example35 (change temperature from 100° C. to 80° C.) starting from8-fluoro-3-(2-methoxy-5-methylphenylsulfonyl)quinoline (150 mg, 0.453mmol) and azetidin-3-ol (99 mg, 1.358 mmol) to give1-(3-(2-methoxy-5-methylphenylsulfonyl)quinolin-8-yl)azetidin-3-ol (11.2mg, yield 6.4%).

LCMS (ESI⁺) m/z [M+H]⁺: 385.10

¹H NMR (CDCl₃, 600 MHz): δ=9.08 (s, 1H), 8.67 (s, 1H), 8.01 (s, 1H),7.45 (t, J=7.9 Hz, 1H), 7.32-7.40 (m, 1H), 7.22-7.29 (m, 1H), 6.78 (d,J=8.3 Hz, 1H), 6.67 (d, J=7.7 Hz, 1H), 4.82 (m, 1H), 4.59-4.67 (m, 2H),4.06 (m, 2H), 3.72 (s, 3H), 2.39 (s, 3H).

Example 41 (3S,4R)-1-[3-(Benzenesulfonyl)-8-quinolyl]piperidine-3,4-diol

The title compound was prepared using the procedure described in example32 (change temperature from 100° C. to 80° C.) starting from8-iodo-3-(phenylsulfonyl)quinoline (800 mg, 2.024 mmol) and(3S,4R)-piperidine-3,4-diol (261 mg, 2.227 mmol) to givetrans-1-(3-(phenylsulfonyl)quinolin-8-yl)piperidine-3,4-diol (38 mg,yield 4.9%).

LCMS (ESI⁺) m/z [M+H]⁺: 385.10

¹H NMR (CDCl₃, 600 MHz): δ=9.19 (s, 1H), 8.80 (s, 1H), 8.03 (d, J=7.5Hz, 2H), 7.59-7.64 (m, 1H), 7.52-7.59 (m, 4H), 7.26 (s, 1H), 4.03 (br.s., 1H), 3.95 (br s, 1H), 3.72 (br s, 1H), 3.44 (br s, 1H), 3.16 (br s,1H), 3.02 (br s, 1H), 2.41 (br s, 1H), 2.03 (br s, 1H).

Example 42(3R,4S)-1-[3-(Benzenesulfonyl)-8-quinolyl]pyrrolidine-3,4-diol

The title compound was prepared using the procedure described in example26 starting from 8-iodo-3-(phenylsulfonyl)quinoline (400 mg, 1.012 mmol)and (3S,4S)-pyrrolidine-3,4-diol (110 mg, 1.012 mmol) to give(3S,4R)-1-(3-(phenylsulfonyl)quinolin-8-yl)pyrrolidine-3,4-diol (7 mg,yield 1.8%, purity 90%).

LCMS (ESI⁺) m/z [M+H]⁺: 371.10

¹H NMR (CDCl₃, 600 MHz): δ=9.05 (s, 1H), 8.66 (s, 1H), 8.02 (m, 2H),7.45-7.65 (several m, 4H), 7.23-7.31 (m, 1H), 6.87 (m, 1H), 4.42 (br.m., 2H), 4.02 (m, 2H), 3.77 (m, 2H).

Example 43cis-1-[3-(Benzenesulfonyl)-8-quinolyl]-3-fluoro-piperidin-4-ol

Rac cis tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (1.5 g,6.84 mmol) was stirred with hydrogen chloride 4M in dioxane at roomtemperature overnight and subsequently concentrated to give(3R,4S)-3-fluoropiperidin-4-ol hydrochloride (1 g, yield 94%).

Rac cis-3-fluoropiperidin-4-ol hydrochloride (1.065 g, 6.84 mmol) wasagitated with MP-carbonate (Macroporous triethylammoniummethylpolystyrene carbonate resin from Biotage) (8.35 g, 27.4 mmol, 3.28mmol/g) at room temperature overnight, filtered, washed and concentratedto give (3R,4S)-3-fluoropiperidin-4-ol (815 mg, yield 100%).2,2-Bis(diphenylphosphino)-1,1-binaphtyl (BINAP) (4.73 mg, 7.59 μmol),tris(dibenzylideneacetone)dipalladium(0) (3.48 mg, 3.8 μmol), cesiumcarbonate (272 mg, 835 μmol), (3R,4S)-3-fluoropiperidin-4-ol (63.3 mg,531 μmol) and 8-iodo-3-(phenylsulfonyl)quinoline (150 mg, 380 mol), wereadded and flushed with argon. To the reaction mixture was added degassedtoluene (5 ml) and stirred at 100° C. for 9 h. The reaction mixture wasdiluted with ethyl acetate, filtered, washed and concentrated. Theresidue was purified using flash chromatography (12 g column; DCM100%→DCM:MeOH 0:100). The product was obtained by preparative HPLCchromatography on a reversed phase column to give to give(3R,4S)-3-fluoro-1-(3-(phenylsulfonyl)quinolin-8-yl)piperidin-4-ol (12.9mg, yield 7.9%, purity 90%).

LCMS (ESI⁺) m/z [M+H]⁺: 387.10

¹H NMR (CDCl₃, 600 MHz): δ=9.23 (s, 1H), 8.76-8.78 (s, 1H), 8.02 (m,2H), 7.5-7.65 (several m, 5H), 7.35 (m, broad, 1H), 4.9-5.05 (br m, 1H),4.19 (m, broad, 1H), 3.75 (br m, 1H), 3.58-3.66 (m, 1H), 3.45 (br m,1H), 3.33-3.38 (m, 1H), 2.05-2.2 (m, broad, 2H).

Example 441-[3-[3-(Trifluoromethyl)phenyl]sulfonyl-8-quinolyl]azetidine-3-carboxylicacid

2,2-Bis(diphenylphosphino)-1,1-binaphtyl (BINAP) (5.38 mg, 8.64 μmol),tris(dibenzylideneacetone)dipalladium(0) (7.91 mg, 8.64 μmol), cesiumcarbonate (619 mg, 1.900 mmol) and8-iodo-3-(3-(trifluoromethyl)phenylsulfonyl)quinoline (400 mg, 0.864mmol) were added and flushed with argon for 6 h. Then tert-butylazetidine-3-carboxylate (136 mg, 0.864 mmol) were dissolved in degassedtoluene (5 ml) and added to the reaction mixture and stirred at 80° C.over the weekend. The reaction mixture was filtered, washed with DCM andconcentrated. The residue was dissolved in DCM and washed several timeswith water. The organic layer was washed with brine, dried with sodiumsulfate, filtered and concentrated. The residue was purified twice usingflash chromatography (12 g column; DCM 100%→DCM:MeOH 0:100) to givetert-butyl1-(3-(3-(trifluoromethyl)phenylsulfonyl)quinolin-8-yl)azetidine-3-carboxylate(53 mg, yield 11.8%, purity 95%).

To a solution of tert-butyl1-(3-(3-(trifluoromethyl)phenylsulfonyl)quinolin-8-yl)azetidine-3-carboxylate(40 mg, 0.081 mmol) in DCM (2 ml) was added TFA (370 mg, 3.25 mmol) at0° C. and stirred at room temperature for 2 h. The reaction mixture wasconcentrated and washed several times with DCM and finally concentratedunder high-vacuum. The residue was dissolved in DCM and washed withbrine. The organic layer was dried with sodium sulfate, filtered andconcentrated. The residue was stirred 3 times with n-pentane anddecanted. The residue was concentrated under high-vacuum to give1-(3-(3-(trifluoromethyl)phenylsulfonyl)quinolin-8-yl)azetidine-3-carboxylicacid (7.1 mg, yield 18.6%, purity 93%).

LCMS (ESI⁺) m/z [M+H]⁺: 437.00

¹H NMR (CDCl₃, 600 MHz): δ=9.05 (s, 1H), 8.70 (s, 1H), 8.28 (s, 1H),8.20 (m, 1H), 7.85 (m, 1H), 7.69 (m, 1H), 7.51 (m, 1H), 7.3 (m, 1H),6.69 (m, 1H), 4.54-4.59 (m, 2H), 4.47 (m, 2H), 3.63-3.69 (m, 1H).

Example 45(3R,4R)-1-[3-(Benzenesulfonyl)-8-quinolyl]pyrrolidine-3,4-diol

The title compound was prepared using the procedure described in example32 (change temperature from 100° C. to 80° C.) starting from8-iodo-3-(phenylsulfonyl)quinoline (400 mg, 1.012 mmol) and(3R,4R)-pyrrolidine-3,4-diol (104 mg, 1.012 mmol) to give(3R,4R)-1-(3-(phenylsulfonyl)quinolin-8-yl)pyrrolidine-3,4-diol (20.8mg, yield 5.6%).

LCMS (ESI⁺) m/z [M+H]⁺: 371.10

¹H NMR (CDCl₃, 600 MHz): δ=9.08 (s, 1H), 8.70 (br s, 1H), 8.02 (m, 2H),7.5-7.6 (several m, 4H), 7.33-7.37 (m, 1H), 6.97 (m, very broad, 1H),4.36 (br m, 2H), 4.23 (m, 2H), 3.71 (m, 2H).

Example 461-[3-(3-Trifluoromethyl-benzenesulfonyl)-quinolin-8-yl]-piperidine-3-carboxylicacid amide Example 471-[3-(3-Cyanophenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylic acid47.1 Preparation of ethyl1-[3-(3-cyanophenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylate

To a solution of PdCl₂(dppf) (5.81 mg, 7.95 μmol), zinc (0.519 mg, 7.95μmol), ethyl1-[3-(3-bromophenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylate (20 mg,0.040 mmol) and dicyanozinc (2.80 mg, 0.024 mmol) in1-methylpyrrolidin-2-one (5 mL) was heated to 140° C. with stirring for16 h. TLC showed the starting compound had been consumed. Then water (5mL) was added, and the mixture was extracted with dichloromethane 3times (3×5 mL). The combined organic phases were washed with brine (3mL), dried over Na₂SO₄ (1 g), then concentrated to give a residue, whichwas purified by Prep-TLC to give the title compound (10 mg, yield 47.9%)as a yellow solid.

47.2 Preparation of1-[3-(3-cyanophenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylic acid

To a solution of ethyl1-[3-(3-cyanophenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylate (10 mg,0.022 mmol) from step 47.2 in tetrahydrofuran (1 mL) was added anaqueous solution of LiOH (1 mL, 1.0 mol/L), and the mixture was stirredat 25° C. for 3 h. LCMS showed that the starting compound had beenconsumed. The reaction was adjusted to pH=6-7 with HCl (1M), thenextracted with ethyl acetate 3 times (3×10 mL). The combined organicphases were washed with brine (10 mL), dried over Na₂SO₄ (1 g), thenconcentrated to give a residue, which was purified by Prep-TLC to givethe title compound (4 mg, yield 40.6%) as yellow solid.

¹H NMR (methanol-d₄ 400 MHz): δ=9.26 (s, 1H), 9.01 (s, 1H), 8.53 (s,1H), 8.38 (br d, J=8.2 Hz, 1H), 8.03 (d, J=8.2 Hz, 1H), 7.80 (t, J=8.0Hz, 1H), 7.74-7.70 (m, 1H), 7.65 (t, J=8.0 Hz, 1H), 7.45 (d, J=7.1 Hz,1H), 3.77 (br d, J=13.0 Hz, 2H), 2.88 (br s, 2H), 2.49 (br s, 1H), 2.07(br s, 4H)

LCMS (ESI+): m/z 422.1 (M+H)⁺

Example 481-[3-(3-Carbamoylphenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylic acid

To a solution of ethyl1-[3-(3-cyanophenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylate (20 mg,0.044 mmol) from step 47.1 of example 47 in tetrahydrofuran (2 mL) wasadded an aqueous solution of NaOH (1 mL, 4.00 mmol), and the mixture wasstirred at 25° C. for 3 h. LCMS showed that the starting compound hadbeen consumed. The mixture was purified with Prep-HPLC to give the titlecompound (3.5 mg, yield 17.61%) as yellow solid.

¹H NMR (methanol-d₄ 400 MHz): δ=12.20 (br s, 1H), 9.28 (d, 1=2.2 Hz,1H), 9.07 (d, J=2.2 Hz, 1H), 8.52 (s, 1H), 8.30 (s, 1H), 8.25 (br d,J=8.4 Hz, 1H), 8.17 (d, J=7.9 Hz, 1H), 7.78-7.74 (m, 2H), 7.68-7.61 (m,2H), 7.34 (d, J=7.5 Hz, 1H), 3.76 (br d, J=11.9 Hz, 2H), 2.85 (br t,J=10.7 Hz, 2H), 2.44 (br s, 1H), 1.98-1.93 (m, 2H), 1.87-1.72 (m, 3H).

LCMS (ESI+): m/z 440.0 (M+H)⁺

Example 491-[3-(3-Carboxyphenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylic acid

To a solution of ethyl1-[3-(3-cyanophenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylate (30 mg,0.067 mmol) from step 47.1 of example 47 in tetrahydrofuran (1 mL) wasadded an aqueous solution of LiOH (1 mL, 1.0 mol/L), and the mixture wasstirred at 25° C. for 3 h. LCMS showed that the starting compound hadbeen consumed. The reaction was purified with Prep-HPLC to give thetitle compound (6 mg, yield 20.4%) as yellow solid.

¹H NMR: (methanol-d₄ 400 MHz): δ=9.44 (d, J=2.4 Hz, 1H), 9.22 (d, J=2.2Hz, 1H), 8.67 (t, J=1.7 Hz, 1H), 8.33 (ddd, J=1.8, 8.0, 9.9 Hz, 2H),8.21 (d, J=7.7 Hz, 1H), 8.08 (d, J=6.8 Hz, 1H), 7.89-7.84 (m, 1H), 7.77(t, J=7.8 Hz, 1H), 3.90 (br d, J=12.3 Hz, 2H), 3.61 (br s, 2H), 2.79(td, J=5.1, 10.1 Hz, 1H), 2.33-2.25 (m, 4H)

LCMS (ESI+): m/z 441.0 (M+H)⁺

Example 50 1-[3-(m-Tolylsulfonyl)-8-quinolyl]piperidine-4-carboxylicacid 50.1 Preparation of ethyl1-[3-(m-tolylsulfonyl)-8-quinolyl]piperidine-4-carboxylate

To a solution of ethyl1-(3-((3-bromophenyl)sulfonyl)quinolin-8-yl)piperidine-4-carboxylate(100 mg, 0.199 mmol) in 1, 4-dioxane (2 mL) and water (0.2 mL) was addedmethylboronic acid (17.84 mg, 0.298 mmol), XPhos Pd G2 catalyst (3.13mg, 3.97 μmol) and Cs₂CO₃ (194 mg, 0.596 mmol). The mixture was heatedat 90° C. with stirring for 16 h under N₂. TLC showed the reaction wascompleted. The reaction was filtered and concentrated to give crudeproduct, which was purified by Prep-HPLC (TFA) to give the titlecompound (100 mg, yield 95%) as yellow powder.

50.2 Preparation of1-[3-(m-tolylsulfonyl)-8-quinolyl]piperidine-4-carboxylic acid

To a solution of ethyl1-[3-(m-tolylsulfonyl)-8-quinolyl]piperidine-4-carboxylate (70 mg, 0.160mmol) from step 50.1 in 1,4-dioxane (2 mL) and water (2 mL) was addedNaOH (12.77 mg, 0.319 mmol). The mixture was stirred for 2 h at 70° C.LCMS showed the reaction was completed. The reaction mixture wasadjusted to pH 4-5 with HCl (1M), then extracted with dichlormethane(3×4 mL), and the combined organic layers were concentrated to drynessto give crude product. The crude product was purified by Prep-HPLC (TFA)to give the title compound (7 mg, yield 10.68%) as yellow powder.

¹H NMR (DMSO-d, 400 MHz): δ=9.24 (d, J=2.4 Hz, 1H), 9.04 (d, J=2.2 Hz,1H), 7.92 (s, 1H), 7.90-7.86 (m, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.64 (t,J=7.9 Hz, 1H), 7.55-7.51 (m, 2H), 7.38 (d, J=7.5 Hz, 1H), 3.76 (br d,J=11.9 Hz, 2H), 2.90 (br t, J=10.7 Hz, 2H), 2.54 (t, J=5.5 Hz, 1H), 2.39(s, 3H), 2.00-1.94 (m, 2H), 1.90-1.78 (m, 2H)

LCMS (ESI+): m/z 411.0 (M+H)⁺

Example 511-[3-[3-(Trifluoromethoxy)phenyl]sulfonyl-8-quinolyl]piperidine-4-carboxylicacid 51.1 Preparation of tert-butyl1-[3-[3-(trifluoromethoxy)phenyl]sulfonyl-8-quinolyl]piperidine-4-carboxylate

To a solution of 8-iodo-3-[3-(trifluoromethoxy)phenyl]sulfonyl-quinoline(70.0 mg, 0.146 mmol) in toluene (5 mL) was added tert-butylpiperidine-4-carboxylate (27.1 mg, 0.146 mmol),(S)—N,N-dimethyl-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethylamine (12.9mg, 0.029 mmol), sodium 2-methylpropan-2-olate (21.1 mg, 0.219 mmol) andtris(dibenzylideneacetone)dipalladium(0) (13.4 mg, 0.015 mmol). Themixture was stirred for 12 h at 90° C. under N₂. TLC (petroleumether/ethyl acetate=3:1, Rf=0.4) showed the reaction worked well. Thesolution was concentrated to afford the crude product, which waspurified by Prep-TLC to give the title compound (50 mg, yield 63.8%) asa yellow solid.

51.2 Preparation of1-[3-[3-(trifluoromethoxy)phenyl]sulfonyl-8-quinolyl]piperidine-4-carboxylicacid

To a solution of tert-butyl1-[3-[3-(trifluoromethoxy)phenyl]sulfonyl-8-quinolyl]-piperidine-4-carboxylate(40 mg, 0.172 mmol) from step 51.1 in CH₂Cl₂ (10 mL) was added2,2,2-trifluoroacetic acid (2 mL). The mixture was stirred for 2 h at25° C. TLC (dichloromethane:methanol=20:1, Rf=0.3) showed the reactionwas completed. The mixture was filtered and concentrated in vacuum. Theresidue was purified by Prep-HPLC to afford the title compound (23 mg,yield 64.2%) as a light yellow solid.

¹H NMR (methanol-d₄, 400 MHz): δ=9.32 (d, J=2.2 Hz, 1H), 9.08 (d, J=2.2Hz, 1H), 8.13 (d, J=7.5 Hz, 1H), 8.04 (s, 1H), 7.89 (br d, J=8.6 Hz,1H), 7.75 (td, J=8.0, 12.3 Hz, 2H), 7.69-7.61 (m, 2H), 3.82 (br d,J=11.7 Hz, 2H), 3.12 (br s, 2H), 2.63-2.59 (m, 1H), 2.18-2.13 (m, 4H)

LCMS (ESI+): m/z 481.2 (M+H)⁺

Example 521-[3-(3-Fluorophenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylic acid52.1 Preparation of 3-(3-fluorophenyl)sulfonyl-8-iodo-quinoline

A solution of 3-(3-fluorophenyl)sulfonylquinolin-8-amine (530 mg, 1.753mmol) in trifluoroacetic acid (2 mL) was stirred at 25° C. for 20 min.Then the mixture was concentrated under reduced pressure to afford aresidue, which was dissolved in acetonitrile (20 mL). tert-Butyl nitrite(271 mg, 2.63 mmol) was added at 0° C., and after stirring for 15 min,copper(I) iodide (668 mg, 3.51 mmol) was added to the mixture at 0° C.Then the mixture was stirred at 25° C. for 1 h. TLC (petroleumether:ethyl acetate=2:1, Rf=0.5) showed that the starting compound (530mg, 1.753 mmol) had been consumed and product had formed. The mixturewas diluted with water (100 mL) and extracted with CH₂Cl₂ (3×200 mL).The organic extracts were dried over Na₂SO₄, filtered, and concentratedunder reduced pressure to give the crude product, which was purified bycolumn chromatography on silica gel (petroleum ether:ethylacetate=80:1=3:1) to give the title compound (500 mg, yield 69.0%) as ayellow solid.

52.2 Preparation of ethyl1-[3-(3-fluorophenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylate

To a mixture of 3-(3-fluorophenyl)sulfonyl-8-iodo-quinoline (300 mg,0.726 mmol) from step 52.1 in toluene (10 mL) and was added sodiumtert-butoxide (140 mg, 1.452 mmol), Pd₂(dba)₃(tris(dibenzylideneacetone)dipalladium(0)) (66.5 mg, 0.073 mmol), ethylpiperidine-4-carboxylate (342 mg, 2.178 mmol) at 25° C. Nitrogen wasbubbled through the mixture for 30 min. Then the mixture was heated at110° C. for 12 h. LCMS showed the reaction worked well. The mixture wasconcentrated under reduced pressure and the residue was purified bycolumn chromatography on silica gel eluted with petroleum ether:ethylacetate=100:1 to 3:1 to give the title compound (100 mg, yield 31.1%) asa yellow solid.

LCMS (ESI+): m/z 443 (M+H)⁺, Rt: 1.263 min.

52.3 Preparation of1-[3-(3-fluorophenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylic acid

To a mixture of ethyl1-[3-(3-fluorophenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylate (0.030g, 0.068 mmol) from step 52.2 in 1, 4-dioxane (6.25 mL) and H₂O (6.25mL) was added NaOH (1.0 g, 25.00 mmol) at 25° C. The solution wasstirred at 68° C. for 1 h.

LCMS showed the reaction worked well. The organic phase was purified byPrep-HPLC to give the title compound (10 mg, yield 35.6%) as a yellowsolid.

¹H NMR (CDCl₃, 400 MHz): δ=9.25 (d, J=2.4 Hz, 1H), 8.79 (d, J=2.4 Hz,1H), 8.07-8.01 (m, 2H), 7.76-7.72 (m, 1H), 7.71-7.60 (m, 2H), 7.23-7.18(m, 2H), 3.92 (br d, J=11.9 Hz, 2H), 3.37 (br s, 2H), 2.76-2.66 (m, 1H),2.32-2.19 (m, 4H)

LCMS (ESI+): m/z 415 (M+H)⁺

Example 531-[3-(3-Pyrrolidin-1-ylphenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylicacid 53.1 Preparation of ethyl1-[3-(3-pyrrolidin-1-ylphenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylate

To a solution of ethyl1-[3-(3-bromophenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylate (100mg, 0.199 mmol) in toluene (2 mL) was added pyrrolidine (141 mg, 1.986mmol), sodium 2-methylpropan-2-olate (38.2 mg, 0.397 mmol), BINAP (12.37mg, 0.020 mmol) and Pd₂(dba)₃ (18.19 mg, 0.020 mmol) into the reactionmixture under N₂ atmosphere. The reaction was stirred for 16 h at 110°C. TLC showed that the starting compound had been consumed. Then water(5 mL) was added, and the mixture was extracted with dichloromethane 3times (3×5 mL). The combined organic phases were washed with brine (3mL), dried over Na₂SO₄ (1 g), and concentrated to give a residue whichwas purified by Prep-TLC to give the title compound (20 mg, yield 20.4%)as a yellow solid.

53.2 Preparation of1-[3-(3-pyrrolidin-1-ylphenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylicacid

To a solution of ethyl1-[3-(3-pyrrolidin-1-ylphenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylate(15 mg, 0.030 mmol) from step 53.1 in dioxane (1 mL) was added anaqueous solution of NaOH (1 mL, 4 M), and the mixture was stirred at 65°C. for 1 h.

LCMS showed that the starting compound had been consumed. The reactionwas purified by Prep-HPLC to give the title compound (9 mg, yield 62.3%)as yellow solid.

¹H NMR (CDCl₃, 400 MHz): δ=9.29 (s, 1H), 8.81 (s, 1H), 7.75 (br d, J=7.9Hz, 1H), 7.66-7.61 (m, 1H), 7.35-7.30 (m, 2H), 7.24-7.20 (m, 1H), 7.12(s, 1H), 6.70 (br d, J=8.4 Hz, 1H), 3.95 (br s, 3H), 3.32 (br s, 5H),2.29 (br s, 5H), 2.04 (br s, 5H)

LCMS (ESI+): m/z 466.0 (M+H)+

Example 541-[3-[3-(3-Methoxypyrrolidin-1-yl)phenyl]sulfonyl-8-quinolyl]piperidine-4-carboxylicacid 54.1 Preparation of ethyl1-[3-[3-(3-benzyloxypyrrolidin-1-yl)phenyl]sulfonyl-8-quinolyl]piperidine-4-carboxylate

To a solution of ethyl1-[3-(3-bromophenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylate (100mg, 0.199 mmol) in toluene (2 mL) was added 3-(benzyloxy)-pyrrolidine(70.4 mg, 0.397 mmol), sodium 2-methylpropan-2-olate (38.2 mg, 0.397mmol), BINAP (12.37 mg, 0.020 mmol) and Pd₂(dba)₃ (18.19 mg, 0.020 mmol)under N₂ atmosphere. The reaction was stirred for 16 h at 110° C. TLCshowed that the starting compound had been consumed. Then water (5 mL)was added, and the mixture was extracted with dichloromethane 3 times(3×5 mL). The combined organic phases were washed with brine (3 mL),dried over Na₂SO₄ (1 g), and concentrated to give a residue which waspurified by Prep-TLC to give the title compound (50 mg, yield 42.0%) asa yellow solid.

54.2 Preparation of1-[3-[3-(3-hydroxypyrrolidin-1-yl)phenyl]sulfonyl-8-quinolyl]piperidine-4-carboxylicacid

To a solution of ethyl1-[3-[3-(3-benzyloxypyrrolidin-1-yl)phenyl]sulfonyl-8-quinolyl]piperidine-4-carboxylate(35 mg, 0.058 mmol) from step 54.1 was added con. HCl (5 mL). Thereaction was stirred at 25° C. for 16 h. LCMS showed that the startingcompound had been consumed. The reaction was purified with Prep-HPLC togive the title compound (27 mg, yield 50.8%) as a yellow solid.

¹H NMR (methanol-d₄, 400 MHz): δ=9.33 (s, 1H), 9.06 (s, 1H), 8.05 (br d,J=8.2 Hz, 1H), 7.89 (br d, J=7.7 Hz, 1H), 7.81-7.76 (m, 1H), 7.41-7.36(m, 1H), 7.26 (d, J=7.3 Hz, 1H), 7.14 (s, 1H), 6.82 (br d, J=7.1 Hz,1H), 3.84 (br d, J=11.9 Hz, 3H), 3.54-3.35 (m, 7H), 3.23 (br d, J=9.9Hz, 2H), 2.75-2.67 (m, 1H), 2.28-2.12 (m, 7H), 2.06 (br s, 1H)

54.3 Preparation of methyl1-[3-[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl-8-quinolyl]piperidine-4-carboxylate

To a stirred solution of1-[3-[3-(3-hydroxypyrrolidin-1-yl)phenyl]sulfonyl-8-quinolyl]piperidine-4-carboxylicacid (10.00 mg, 0.021 mmol) from step 54.2 in dimethyl formamide (2 mL)was added sodium hydride (0.997 mg, 0.042 mmol) at 0° C. The mixture wasstirred for 15 min, then iodomethane (8.84 mg, 0.062 mmol) was slowlyadded and the reaction was stirred for 10 h at 25° C. TLC showed thereaction was completed. The reaction was diluted with water (2 mL) andextracted with dichloromethane (3×3 mL). The combined organic phaseswere washed with water (6 mL), brine (3 mL), dried over Na₂SO₄ (1 g) andconcentrated in vacuum to give crude product of the title compound (10mg, yield 94%), which was used in the next step without any furtherpurification.

54.4 Preparation of1-[3-[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl-8-quinolyl]-piperidine-4-carboxylicacid

To a stirred solution of methyl1-[3-[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl-8-quinolyl]piperidine-4-carboxylate(10.00 mg, 0.020 mmol) from step 54.3 in tetrahydrofuran (0.5 mL) andwater (0.5 mL) was added lithium hydroxide (0.470 mg, 0.020 mmol). Themixture was stirred for 8 h at 25° C. The reaction was adjusted to pH4-5 with HCl (1M) and extracted with dichloromethane (3×2 mL). Thecombined organic phases were washed with water (5 mL), brine (5 mL),dried over Na₂SO₄ (0.5 g) and concentrated in vacuum. The crude productwas purified by Prep-HPLC (TFA) to give the title compound (5.7 mg,yield 58.6%) as a yellow oil.

¹H NMR (methanol-d₄, 400 MHz,): δ=9.35 (d, J=2.2 Hz, 1H), 9.07 (d, J=2.2Hz, 1H), 8.05 (d, J=8.3 Hz, 1H), 7.89-7.84 (m, 1H), 7.83-7.76 (m, 1H),7.44-7.38 (m, 1H), 7.29 (d, J=7.9 Hz, 1H), 7.17 (s, 1H), 6.85 (br d,J=7.9 Hz, 1H), 4.17 (br s, 1H), 3.87 (br d, J=12.3 Hz, 2H), 3.53 (dd,J=4.8, 10.5 Hz, 1H), 3.43-3.39 (m, 3H), 3.38 (s, 3H), 2.75-2.69 (m, 1H),2.31-2.09 (m, 7H)

LCMS (ESI+): m/z 496.1 (M+H)⁺

Example 551-[3-(3-Piperazin-1-ylphenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylicacid 55.1 Preparation of ethyl1-[3-(3-piperazin-1-ylphenyl)sulfonyl-8-quinolyl]-piperidine-4-carboxylate

To a solution of ethyl1-[3-(3-bromophenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylate (100mg, 0.199 mmol) in toluene (4 mL) was added piperazine (86 mg, 0.993mmol), sodium 2-methylpropan-2-olate (38.2 mg, 0.397 mmol), BINAP (12.37mg, 0.020 mmol) and Pd₂(dba)₃ (18.19 mg, 0.020 mmol) under N₂atmosphere. The mixture was stirred at 110° C. for 16 h. LCMS showedthat the starting compound had been consumed. The mixture was filtered,then concentrated and purified with Prep-HPLC to give the title compound(50 mg, yield 43.5%) as a yellow solid.

55.2 Preparation of1-[3-(3-piperazin-1-ylphenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylicacid

To a solution of ethyl1-[3-(3-piperazin-1-ylphenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylate(30 mg, 0.059 mmol) from step 55.1 in dioxane (1 mL) was added aqueousNaOH (1 mL, 4 M), and the reaction was stirred at 65° C. for 1 h. LCMSshowed that the starting compound was consumed. The reaction waspurified with Prep-HPLC to give the title compound (12 mg, yield 41.9%)as a yellow solid.

¹H NMR (D₂O, 400 MHz): δ=9.38 (s, 1H), 9.19 (d, J=2.2 Hz, 1H), 8.25 (dd,J=8.1, 14.7 Hz, 2H), 7.92 (t, J=8.1 Hz, 1H), 7.73 (s, 1H), 7.69-7.66 (m,1H), 7.64-7.59 (m, 1H), 7.42 (br d, J=7.9 Hz, 1H), 3.92 (br d, J=12.3Hz, 2H), 3.82-3.72 (m, 2H), 3.60-3.56 (m, 4H), 3.47-3.43 (m, 4H), 2.83(br t, J=10.3 Hz, 1H), 2.42-2.24 (m, 4H)

LCMS (ESI+): m/z 481.1 (M+H)⁺

Example 561-[3-[3-(4-Methylpiperazin-1-yl)phenyl]sulfonyl-8-quinolyl]piperidine-4-carboxylicacid

To a solution of ethyl1-[3-(3-bromophenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylate (100mg, 0.199 mmol) in toluene (2 mL) was added 1-methylpiperazine (99 mg,0.993 mmol), sodium 2-methylpropan-2-olate (38.2 mg, 0.397 mmol), BINAP(12.37 mg, 0.020 mmol) and Pd₂(dba)₃ (18.19 mg, 0.020 mmol) under N₂atmosphere.

The reaction was stirred at 110° C. for 16 h. LCMS showed that thestarting compound was consumed. The reaction was filtered, thenconcentrated and purified by Prep-HPLC to give the title compound (6 mg,yield 6.1%) as a yellow solid.

¹H NMR (D₂O, 400 MHz): δ=9.34 (d, J=2.3 Hz, 1H), 9.14 (d, J=2.3 Hz, 1H),8.25 (t, J=7.3 Hz, 2H), 7.89 (t, J=8.1 Hz, 1H), 7.65 (d, J=2.1 Hz, 1H),7.62-7.52 (m, 2H), 7.35 (dd, J=1.8, 8.2 Hz, 1H), 3.95-3.80 (m, 6H), 3.62(br d, J=1 1.4 Hz, 2H), 3.28-3.13 (m, 4H), 2.98-2.88 (m, 4H), 2.45-2.25(m, 4H)

LCMS (ESI+): m/z 495.1 (M+H)⁺

Example 572-[1-[3-[3-(Trifluoromethyl)phenyl]sulfonyl-8-quinolyl]-4-piperidyl]aceticacid 57.1 Preparation of methyl2-[1-[3-[3-(trifluoromethyl)phenyl]sulfonyl-8-quinolyl]-4-piperidyl]acetate

To a solution of 8-iodo-3-[3-(trifluoromethyl)phenyl]sulfonyl-quinoline(250 mg, 0.540 mmol) in dimethyl formamide (3 mL) was added methyl2-(piperidin-4-yl)acetate (255 mg, 1.619 mmol), sodium tert-butoxide(207 mg, 2.159 mmol), Pd₂(dba)₃ (49.4 mg, 0.054 mmol). Nitrogen wasbubbled through the mixture for 30 min. Then the reaction was heated at120° C. for 12 h. LCMS showed the reaction worked well. The mixture wasconcentrated under reduced pressure and the residue was purified byPrep-TLC to give the title compound (120 mg, yield 45.1%) as a yellowsolid.

LCMS (ESI+): m/z 493.1 (M+H)⁺, Rt: 2.246 min.

57.2 Preparation of2-[1-[3-[3-(trifluoromethyl)phenyl]sulfonyl-8-quinolyl]-4-piperidyl]aceticacid

To a solution of methyl2-[1-[3-[3-(trifluoromethyl)phenyl]sulfonyl-8-quinolyl]-4-piperidyl]acetat(100 mg, 0.203 mmol) from step 57.1 in 1, 4-dioxane (2 mL) and H₂O (2mL) was added NaOH (300 mg, 7.500 mmol). Then the mixture was heated at65° C. for 1 h. LCMS showed that the starting compound was consumed andthe desired product generated. The reaction mixture was purified byPrep-HPLC to give the title compound (37 mg, yield 38.1%).

¹H NMR (methanol-d₄, 400 MHz): δ=9.46 (d, J=2.2 Hz, 1H), 9.26 (d, J=2.2Hz, 1H), 8.43-8.39 (m, 2H), 8.22 (d, J=7.9 Hz, 1H), 8.13 (d, J=7.9 Hz,1H), 8.04 (d, J=8.3 Hz, 1H), 7.91-7.83 (m, 2H), 3.87 (br d, J=11.8 Hz,2H), 3.63 (br t, J=11.6 Hz, 2H), 2.43 (d, J=7.0 Hz, 2H), 2.26-2.12 (m,3H), 1.97-1.84 (m, 2H)

LCMS (ESI+): m/z 478.5 (M+H)⁺

Example 582-[1-[3-[3-(Trifluoromethyl)phenyl]sulfonyl-8-quinolyl]-3-piperidyl]aceticacid

The title compound was prepared in analogy to example 57 starting frommethyl 2-(piperidin-3-yl)acetate.

LCMS (ESI+): m/z 478.5 (M+H)⁺

II. Biological Investigations

Displacement of radioligands binding to the following cloned humanreceptors

1. Preparation of Membranes by Ultrasonic Treatment and DifferentialCentrifugation

Cells from stable clonal cell lines expressing the correspondingreceptor (5-HT₆, α₁-adrenergic, dopamine D₂ or histamine H₁ receptors)were washed with PBS (w/o Ca⁺⁺, Mg⁺⁺) and harvested in PBS with 0.02%EDTA. The cells were collected by centrifugation at 500 g for 10 min. at4° C., washed with PBS and centrifuged (500 g, 10 min. 4° C.). Thepellets were stored at −80° C. until use. For membrane preparation, thethawed cell pellet was resuspended in ice-cold sucrose buffer (0.25 Msucrose, 10 mM Hepes (pH 7.4), 1 mM Phenylmethylsulfonyl fluoride (PMSF)in DMSO, 5 μg/ml Pepstatin-A, 3 mM EDTA, 0.025% Bacitracin) andhomogenized with a Branson Sonifier W-250 (Settings: Timer 4; OutputControl 3; Duty Cycle constant; 2 to 3 cycles). Cell disruption waschecked with the aid of a microscope. Remaining unbroken cells werepelleted at 1.000 g for 10 min. at 4° C. The sucrose buffer supernatantwas then centrifuged at 60.000 g for 1 h at 4° C. (BeckmanUltrazentrifuge XL 80). The pellet was resuspended in 30 ml ice-coldTris buffer (20 mM TRIS (pH 7.4), 5 μg/ml Pepstatin A, 0.1 mM PMSF, 3 mMEDTA) by pipetting through a 10 ml serological pipet and centrifuged for1 h at 4° C. at 60.000 g. A final resuspension was performed in a smallvolume of ice-cold Tris buffer (see above) by pressing through aserological pipet followed by ultrasonic treatment with a BransonSonifier W-250 (Settings: Timer 1; Output Control 3; Duty Cycleconstant; 1 cycle). Protein concentration was determined (BCA-Kit;Pierce) and aliquots stored at −80° C. or in liquid nitrogen forlong-term storage.

2. Receptor Binding Experiments

All receptor binding experiments were carried out in the correspondingassay buffer in a total volume of 200 μl in the presence of variousconcentrations of test compound (10⁻⁵ M to 10⁻⁹ M, tenfold serialdilution, duplicate determinations). The assays were terminated byfiltration on polyethylenimine (PEI 0.1% or 0.3%) presoaked PackardUnifilter Plates (GF/C or GF/B) with a Tomtec MachIII U 96 well-plateharvester. After the plates had been dried for 2 h at 55° C. in a dryingchamber scintillation cocktail (BetaPlate Scint; PerkinElmer) was added.Radioactivity was measured in a Microbeta Trilux two hours after theaddition of the scintillation mixture. Data derived from liquidscintillation counting were analysed by iterative non-linear regressionanalysis with the use of the Statistical Analysis System (SAS): aprogram similar to “LIGAND” as described by Munson and Rodbard(Analytical Biochemistry 107, 220-239 (1980).

a) 5-HT₆ Receptor Binding Assay

HEK293 cells stably expressing the h-5-HT₆ receptor (NCBI ReferenceSequence XM 001435) were cultured in RPMI1640 medium supplemented with25 mM HEPES, 10% fetal calf serum and 1-2 mM glutamine. The membranepreparation was performed as described in section 1. For these membranesa K_(D) of 1.95 nM for [³H]-LSD (Lysergic Acid Diethylamide; Amersham,TRK1038) was determined by means of saturation binding experiments. Onthe day of the assay, the membranes were thawed, diluted in assay buffer(50 mM Tris-HCl, 5 mM CaCl₂, 0.1% ascorbic acid, 10 μM pargyline, pH7.4) to a concentration of 8 μg protein/assay and homogenized by gentlevortexing For inhibition studies, 1 nM [³H]-Lysergic Acid Diethylamidewas incubated in the presence of various concentrations of test compoundin assay buffer. Non-specific binding was defined with 1 μMmethiothepin. The binding reaction was carried out for 3.5 h at roomtemperature. During the incubation, the plates were shaken on a plateshaker at 100 rpm and terminated by filtration on Packard Unifilter GF/C(0.1% PEI) plates, followed by 2 wash cycles with ice-cold 50 mMTris-HCl, 5 mM CaCl₂.

b) Dopamine D₂ Receptor Binding Assay

HEK293 cells stably expressing the dopamine D₂ receptor (NCBI ReferenceSequence NM_000795) were cultured in RPMI1640 medium supplemented with25 mM HEPES, 10% fetal calf serum and 1-2 mM glutamine. The membranepreparation was performed as described in section 1. For these membranesa K_(D) of 0.22 nM for [¹²⁵I]-iodospiperone (PerkinElmer Life Sciences,NEX284) was determined by means of saturation binding experiments. Onthe day of the assay, the membranes were thawed, diluted in assay buffer(50 mM Tris-HCl, 120 mM NaCl, 5 mM MgCl₂, 5 mM KCl, 1.5 mM CaCl₂, pH7.4) to a concentration of 15 μg protein/assay and homogenized by gentlevortexing. For inhibition studies, 0.01 nM [¹²⁵I]-iodospiperone(PerkinElmer Life Sciences, NEX284) was incubated in the presence ofvarious concentrations of test compound in assay buffer. Non-specificbinding was defined with 1 μM haloperidol. The binding reaction wascarried out for 1 h at room temperature and terminated by filtration onPackard Unifilter GF/B (0.1% PEI) plates, followed by 6 wash cycles withan ice-cold 7% polyethylenglycol solution.

c) α₁-Adrenergic Receptor Binding Assay

CHO-K₁ cells stably expressing the al-adrenergic receptor (NCBIReference Sequence NM_033303) were cultured in RPMI1640 mediumsupplemented with 25 mM HEPES, 10% fetal calf serum and 1-2 mMglutamine. The membrane preparation was performed as described insection 1. For these membranes a K_(D) of 0.12 nM for [³H]-prazosine(PerkinElmer Life Sciences, NET823) was determined by means ofsaturation binding experiments. On the day of the assay, the membraneswere thawed, diluted in assay buffer (50 mM Tris-HCl, pH 7.4) to aconcentration of 4 μg protein/assay and homogenized by gentle vortexing.For inhibition studies, 0.1 nM [³H]-prazosine (PerkinElmer LifeSciences, NET823) was incubated in the presence of variousconcentrations of test compound in assay buffer. Non-specific bindingwas defined with 1 μM phentolamine. The binding reaction was carried outfor 1 h at room temperature and terminated by filtration on PackardUnifilter GF/C (0.1% PEI) plates, followed by 3 wash cycles withice-cold assay buffer.

d) H₁ Receptor Binding Assay

CHO-K₁ cells stably expressing the histamine H₁ receptor(Euroscreen-ES-390-C, NCBI Reference Sequence NM_000861) were culturedin RPMI1640 medium supplemented with 25 mM HEPES, 10% fetal calf serumand 1-2 mM glutamine. The membrane preparation was performed asdescribed in section 1. For these membranes a K_(D) of 0.83 nM for[³H]-pyrilamine (PerkinElmer Life Sciences, NET594) was determined bymeans of saturation binding experiments. On the day of the assay, themembranes were thawed, diluted in assay buffer (50 mM Na₂HPO₄, 50 mMKH₂PO₄, pH 7.4) to a concentration of 6 μg protein/assay and homogenizedby gentle vortexing. For inhibition studies, 1 nM [³H]-pyrilamine(PerkinElmer Life Sciences, NET594) was incubated in the presence ofvarious concentrations of test compound in assay buffer. Non-specificbinding was defined with 1 μM pyrilamine. The binding reaction wascarried out for 50 minutes at room temperature and terminated byfiltration on Packard Unifilter GF/C (0.3% PEI) plates, followed by 2wash cycles with ice-cold assay buffer.

3. Data Analysis

Data derived from liquid scintillation counting were analyzed byiterative non-linear regression analysis with the use of the StatisticalAnalysis System (SAS): a program similar to “LIGAND” as described byMunson and Rodbard (Anal. Biochem. 1980, 107, 220-239). Fitting wasperformed according to formulae described by Feldman (Anal. Biochem.1972, 48, 317-338). IC₅₀, nH and K_(i) values were expressed asgeometrical mean. For receptors with a low affinity for the testcompound, where the highest tested compound concentration inhibited lessthan 30% of specific radioligand binding, K_(i)-values were determinedaccording to the equation of Cheng and Prusoff (Biochem. Pharmacol.1973, 22, 2099-2108) and expressed as greater than (>).

The results of the receptor binding studies are expressed as receptorbinding constants K_(i)(5-HT₆), K_(i)(D₂), K_(i)(α₁-adrenergic) andK_(i)(H₁), respectively, as described herein before, and given in table1.

4. Metabolic Stability

Samples of the tested compounds (0.5 μM) were preincubated together withhuman liver microsomes (0.25 mg of microsomal protein/mL) in 0.05 Mpotassium phosphate buffer of pH 7.4 in microtiter plates at 37° C. for5 minutes. The reaction was started by adding NADPH (1.0 mM). After 0,5, 10, 15, 20 and 30 minutes, an aliquot was removed, the reaction wascooled and stopped by adding twice the amount of quench solutionconsisting of acetonitrile/methanol 1:1, and containing 0.2 μMcarbutamide as internal standard. The samples were frozen untilanalyzed. The remaining concentration of undegraded test substance wasdetermined by liquid chromatography-tandem mass spectrometry (LC-MS/MS).The half-life (t_(1/2)) was determined from the gradient of the ratio ofthe signal of (test substance/internal standard)/unit time plot,allowing the calculation of the half-life of the test substance,assuming first order kinetics, from the decrease in the concentration ofthe compound with time. The microsomal clearance (mClint) was calculatedas follows: mClint=((ln(2)/t ½)/Microsomal Protein Concentration(mg/ml))*1000, leading to the unit of μL/min/mg.

TABLE 1 Ki (5-HT₆) mClint # [nM] [μl/min/mg] 1 +++ ++ 2 +++ + 3 +++ +++4 +++ + 5 +++ + 6 ++ +++ 7 +++ + 8 +++ ++ 9 +++ +++ 10 +++ ++ 11 ++ 12++ +++ 13 +++ + 14 ++ 15 + +++ 16 ++ ++ 18 +++ +++ 19 ++ ++ 20 +++ ++ 21++ + 22 ++ ++ 23 +++ ++ 24 ++ + 25 ++ 26 +++ 27 +++ ++ 28 ++ ++ 29 ++++++ 30 +++ + 31 ++ +++ 32 +++ ++ 33 +++ ++ 34 +++ +++ 35 ++ 36 +++ +++37 ++ +++ 38 + 39 ++ + 40 ++ 41 +++ +++ 42 +++ +++ 44 ++ +++ 45 +++ +++46 +++ 47 +++ 49 +++ 50 +++ 51 ++ 52 ++ 53 ++ 54 +++ 55 +++ 56 +++ 57+++ 58 ++ Key: Ki (5-HT₆) mClint + 100-<500 nM from 60 to <120 μl/min/mg++ 10-<100 nM from 30 to <60 μl/min/mg +++ <10 nM <30 μl/min/mg5. Blocking the hERG Channel

Cell Culture System

Human embryonic kidney (HEK-293) cells, stably transfected with the hERGchannel, were obtained from Dr. C. W. January, Cardiology Division,University of Wisconsin. Cells were maintained at 37° C. (5% CO₂atmosphere) in MEM media, supplemented with 2 mM L-glutamine, 0.1 mMnonessential amino acids, 1 mM sodium pyruvate, 1%penicillin/streptomycin, 10% FBS and 0.2 mg/mL Geneticin. Cells werecryo-preserved in 90% FBS 10% DMSO at a concentration of 10 millioncells per mL. For electrophysiological studies, cells were thawed,resuspended in CHO serum free media and immediately added to theinstrument on the day of study.

Experimental Solutions

The bath solution contained (in mM): 140 NaCl, 5 KCl, 1 MgCl2, 2 CaCl₂,5 glucose, 20 HEPES, pH=7.4. The internal solution contained (in mM):125 K-aspartate, 20 KCl, 10 EGTA, 5 MgATP, 1 MgCl₂, 5 HEPES, pH=7.3.Stock solution (100 mM) of the tested compounds was prepared fresh. Analiquot of stock solution was added to the bath solution to attaintargeted compound concentrations of 10, 30 or 100 μM. The DMSOconcentration never exceeded 0.1% in the superfusate.

Electrophysiology Workstation and Experimental Protocol

Currents were recorded using PatchXpress (Molecular Devices), anautomated planar patch-clamp system and a 16-well Sealchip positioneddirectly on top of the headstage. To obtain high resistant seals, cellswere added to each chamber and allowed to settle for 10 s. Negativepressure was then applied to promote cell delivery to the patch chipopenings on the chamber bottom. After formation of gigaohm seals,negative pressure ramps were applied to obtain intracellular access.Access resistance was initially optimized by additional pressure rampsto assure the intracellular access was adequate for voltage clampexperiments (targeted access resistance <10 MΩ). Whole-cell compensationand series resistance compensation were used at 60%. Experiments usingPatchXpress were conducted at room temperature; however, the temperatureinside the instrument was slightly elevated at the headstage owing tounavoidable heat generated by the instrument. During a five-minuteequilibration period, a two-second depolarizing pulse to +40 mV,followed by a two-second repolarizing pulse to −50 mV was applied onceevery 15 seconds from a holding potential of −80 mV. Cells were exposedto three ascending concentrations of drug.

The compounds of following examples were tested: 3, 5, 8, 9, 13, 18, 23,24, 27, 34, 41 and 45. All compounds had values of more than 10 μM.

1.-23. (canceled)
 24. A method for treating disorders which respond tothe modulation of the 5-HT₆ receptor, which method comprisesadministering to a subject in need thereof at least one compound offormula (I)

wherein R¹ is selected from the group consisting of a ring R^(a),halogen, C₁-C₂-haloalkyl, C₁-C₂-alkoxy, C₁-C₂-haloalkoxy, an N-boundsaturated 3-, 4-, 5-, 6-, 7- or 8-membered heteromonocyclic ringcontaining one or two nitrogen atoms as ring members; and an N-boundsaturated 7-, 8-, 9-, 10-, 11- or 12-membered heterobicyclic ringcontaining one or two nitrogen atoms as ring members; where theheteromonocyclic ring and the heterobicyclic ring may carry one or moresubstituents R⁴; R² is selected from the group consisting of a phenylring, a naphthyl ring, a 5- or 6-membered monocyclic heteroaromatic ringcontaining 1, 2, 3 or 4 heteroatoms selected from the group consistingof N, O and S as ring members, and a 9- or 10-membered bicyclicheteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected fromthe group consisting of N, O and S as ring members, where the phenyl,the naphthyl and the monocyclic or bicyclic heteroaromatic ring maycarry one ring R^(a) and/or one or more substituents R⁵; with theproviso that R¹ is R^(a) if the ring R² is not substituted by R^(a);each R³ is independently selected from the group consisting of halogen,cyano, nitro, hydroxyl, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy,C₁-C₆-haloalkoxy, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,C₁-C₆-haloalkylsulfonyl, formyl, C₁-C₆-alkylcarbonyl,C₁-C₆-haloalkylcarbonyl, C₁-C₆-alkoxycarbonyl, C₁-C₆-haloalkoxycarbonyl,aminocarbonyl, C₁-C₆-alkylaminocarbonyl anddi-(C₁-C₆-alkyl)-aminocarbonyl; each R⁴ is independently selected fromthe group consisting of halogen, cyano, nitro, C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₃-C₆-cycloalkyl, C₃-C₆-halocycloalkyl,C₁-C₆-alkylthio, C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl,C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyland oxo; each R⁵ is independently selected from the group consisting ofhalogen, cyano, nitro, hydroxyl, C₁-C₆-alkyl, C₁-C₆-haloalkyl,C₃-C₆-cycloalkyl, C₃-C₆-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkylthio, C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl,C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl,formyl, C₁-C₆-alkylcarbonyl, C₁-C₆-haloalkylcarbonyl, carboxyl,carboxyl-C₁-C₂-alkyl, C₁-C₆-alkoxycarbonyl, C₁-C₆-haloalkoxycarbonyl,amino, C₁-C₆-alkylamino, di-(C₁-C₆-alkyl)-amino, aminocarbonyl,C₁-C₆-alkylaminocarbonyl, di-(C₁-C₆-alkyl)-aminocarbonyl, phenyl whichmay carry one or more substituents R⁶; and a 3-, 4-, 5-, 6-, 7- or8-membered saturated, partially unsaturated or maximally unsaturatedheterocyclic ring containing 1, 2 or 3 heteroatoms or heteroatom groupsselected from the group consisting of N, O, S, NO, S(O) and S(O)₂ asring members, where the heterocyclic ring may carry one or moresubstituents R⁷; each R⁶ is independently selected from the groupconsisting of halogen, cyano, nitro, hydroxyl, C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₃-C₆-cycloalkyl, C₃-C₆-halocycloalkyl, C₁-C₆-alkoxy,C₁-C₆-haloalkoxy, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,C₁-C₆-haloalkylsulfonyl, formyl, C₁-C₆-alkylcarbonyl,C₁-C₆-haloalkylcarbonyl, carboxyl, carboxyl-C₁-C₂-alkyl,C₁-C₆-alkoxycarbonyl, C₁-C₆-haloalkoxycarbonyl, amino, C₁-C₆-alkylamino,di-(C₁-C₆-alkyl)-amino, and —C(O)N(R⁸)R⁹; each R⁷ is independentlyselected from the group consisting of halogen, cyano, nitro,C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₆-cycloalkyl, C₃-C₆-halocycloalkyl,C₁-C₆-alkylthio, C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl,C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl,formyl, C₁-C₆-alkylcarbonyl, C₁-C₆-haloalkylcarbonyl,C₁-C₆-alkoxycarbonyl, C₁-C₆-haloalkoxycarbonyl, amino, C₁-C₆-alkylaminoand di-(C₁-C₆-alkyl)-amino; R⁸ and R⁹, independently of each other andindependently of each occurrence, are selected from the group consistingof hydrogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl,C₃-C₆-halocycloalkyl, C₃-C₆-cycloalkyl-C₁-C₄-alkyl,C₃-C₆-halocycloalkyl-C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, phenyland benzyl; or R⁸ and R⁹, together with the nitrogen atom they are boundto, form a 3-, 4-, 5-, 6-7- or 8-membered saturated heterocyclic ringwhich may contain 1, 2 or 3 additional heteroatoms or heteroatom groupsselected from the group consisting of N, O, S, NO, S(O) and S(O)₂ wherethe ring may carry 1, 2 or 3 substituents selected from the groupconsisting of halogen, cyano, nitro, hydroxyl, C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₃-C₆-cycloalkyl, C₃-C₆-halocycloalkyl, C₁-C₆-alkoxy,C₁-C₆-haloalkoxy, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,C₁-C₆-haloalkylsulfonyl, formyl, C₁-C₆-alkylcarbonyl,C₁-C₆-haloalkylcarbonyl, carboxyl, C₁-C₆-alkoxycarbonyl andC₁-C₆-haloalkoxycarbonyl; L is S(O)₂, CH₂—S(O)₂, S(O)₂—CH₂, C(O)—NH,NH—C(O), NH—S(O)₂ or S(O)₂—NH; R^(a) is an N-bound saturated 3-, 4-, 5-,6-, 7- or 8-membered heteromonocyclic ring containing one nitrogen atomas ring member; or an N-bound saturated 7-, 8-, 9-, 10-, 11- or12-membered heterobicyclic ring containing one nitrogen atom as ringmember, where the heteromonocyclic or heterobicyclic ring carries 1, 2or 3 substituents R^(b) and optionally 1 or 2 further substituents R⁴;R^(b) is an oxygen-containing radical independently selected from thegroup consisting of hydroxyl, C₁-C₄-alkoxy, —C(O)OH, —CH₂—C(O)OH and—C(O)N(R⁸)R⁹; and m is 0, 1 or 2; or an N-oxide, a tautomeric form, astereoisomer or a pharmaceutically acceptable salt thereof.
 25. Themethod as claimed in claim 24, where the disorders are selected from thegroup consisting of diseases of the central nervous system, addictionand obesity.
 26. The method as claimed in claim 25, where the disease ofthe central nervous system is a cognitive dysfunction.
 27. The method asclaimed in claim 26, where the cognitive dysfunction is associated withAlzheimer's disease.
 28. The method as claimed in claim 26, where thecognitive dysfunction is associated with schizophrenia.
 29. The methodas claimed in claim 24, R¹ is R^(a), where R^(a) is an N-bound saturated3-, 4-, 5-, 6-, 7- or 8-membered heteromonocyclic ring containing onenitrogen atom as ring member, where the heteromonocyclic ring carries 1,2 or 3 substituents R^(b) and optionally 1 or 2 further substituents R⁴.30. The method as claimed in claim 24, R¹ is R^(a), where R^(a) is anN-bound saturated 7-, 8-, 9-, 10-, 11- or 12-membered heterobicyclicring containing one nitrogen atom as ring member, where theheterobicyclic ring carries 1, 2 or 3 substituents R^(b) and optionally1 or 2 further substituents R⁴.
 31. The method as claimed in claim 24,where R¹ is halogen; and the phenyl, naphthyl, monocyclic or bicyclicheteroaromatic ring R² carries one substituent R^(a) and optionally alsoone or more substituents R⁵
 32. The method as claimed in claim 24, whereR¹ is an N-bound saturated 3-, 4-, 5-, 6-, 7- or 8-memberedheteromonocyclic ring containing one or two nitrogen atoms as ringmembers; or an N-bound saturated 7-, 8-, 9-, 10-, 11- or 12-memberedheterobicyclic ring containing one or two nitrogen atoms as ringmembers; where the heteromonocyclic ring and the heterobicyclic ring maycarry one or more substituents R⁴; and the phenyl, naphthyl, monocyclicor bicyclic heteroaromatic ring R² carries one substituent R^(a) andoptionally also one or more substituents R⁵.
 33. The method as claimedin claim 24, where the oxygen-containing radical R^(b) is selected fromthe group consisting of hydroxyl (—OH), carboxyl (—C(O)OH), —CH₂—C(O)OHand —C(O)NH₂
 34. The method as claimed in claim 24, where L is S(O)₂.35. The method as claimed in claim 24, where R² is optionallysubstituted phenyl.
 36. The method as claimed in claim 24, where m is 0.37. The method of claim 24, where the compound of formula (I) is acompound of formula (I.1)


38. The method of claim 37, where R¹ is R^(a), which is in turn anN-bound saturated heterocyclic ring selected from the group consistingof azetidin-1-yl, pyrrolidin-1-yl and piperidine-1-yl, where the ringcarries one or two substituents R^(b); and carries optionally one or twosubstituents R⁴; and R² is phenyl which may be substituted by 1 or 2substituents selected from the group consisting of halogen, cyano,hydroxyl, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,COOH, CONH₂ and an N-bound saturated heterocyclic ring selected from thegroup consisting of azetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl andpiperazin-1-yl, where the heterocyclic ring carries one or twosubstituents selected from the group consisting of C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₁-C₆-alkoxy, OH and COOH.
 39. A method for treatingdisorders which respond to the modulation of the 5-HT₆ receptor, whichmethod comprises administering to a subject in need thereof at least onecompound selected from the group consisting of1-[3-(3-Trifluoromethyl-benzenesulfonyl)-quinolin-8-yl]-piperidin-4-ol;1-[3-(3-Trifluoromethyl-benzenesulfonyl)-quinolin-8-yl]-pyrrolidin-3-ol;1-[3-(3-Trifluoromethyl-benzenesulfonyl)-quinolin-8-yl]-piperidine-4-carboxylicacid;(S)-1-[3-(3-Trifluoromethyl-benzenesulfonyl)-quinolin-8-yl]-piperidin-3-ol;(R)-1-[3-(3-Trifluoromethyl-benzenesulfonyl)-quinolin-8-yl]-piperidin-3-ol;1-[3-(3-Trifluoromethyl-benzenesulfonyl)-quinolin-8-yl]-piperidine-3-carboxylicacid;4-Methyl-1-[3-[3-(trifluoromethyl)phenyl]sulfonyl-8-quinolyl]piperidin-4-ol;1-[3-[3-(Trifluoromethyl)phenyl]sulfonyl-8-quinolyl]azetidin-3-ol;1-[3-(3-Fluorophenyl)sulfonyl-8-quinolyl]piperidin-4-ol;1-[3-(3-Fluorophenyl)sulfonyl-8-quinolyl]azetidin-3-ol;(3S)-1-[3-[3-(Trifluoromethyl)phenyl]sulfonyl-8-quinolyl]pyrrolidine-3-carboxylicacid;(3R)-1-[3-[3-(Trifluoromethyl)phenyl]sulfonyl-8-quinolyl]pyrrolidine-3-carboxylicacid; 1-[3-(3-Methoxyphenyl)sulfonyl-8-quinolyl]piperidin-4-ol;1-[3-(3-Methoxyphenyl)sulfonyl-8-quinolyl]azetidin-3-ol;1-[3-(3-Methoxyphenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylic acid;1-[3-[[8-(4-Hydroxy-1-piperidyl)-3-quinolyl]sulfonyl]phenyl]piperidin-4-ol;1-[3-[[8-(4-Carboxy-1-piperidyl)-3-quinolyl]sulfonyl]phenyl]piperidine-4-carboxylicacid; 1-[3-(Benzenesulfonyl)-8-quinolyl]piperidin-4-ol;(3R)-1-[3-[3-(Trifluoromethyl)phenyl]sulfonyl-8-quinolyl]pyrrolidin-3-ol;(3R)-1-[3-(3-Fluorophenyl)sulfonyl-8-quinolyl]piperidin-3-ol;1-[3-(2-Methoxyphenyl)sulfonyl-8-quinolyl]piperidin-4-ol;(3S)-1-[3-(Benzenesulfonyl)-8-quinolyl]piperidin-3-ol;(3R)-1-[3-(Benzenesulfonyl)-8-quinolyl]piperidin-3-ol;1-[3-[(8-Fluoro-3-quinolyl)sulfonyl]phenyl]piperidin-4-ol;1-[2-[(8-Fluoro-3-quinolyl)sulfonyl]phenyl]piperidin-4-ol;(3S)-1-[3-(3-Fluorophenyl)sulfonyl-8-quinolyl]pyrrolidin-3-ol;(3S)-1-[3-(3-Fluorophenyl)sulfonyl-8-quinolyl]piperidin-3-ol;1-[3-(2-Hydroxy-5-methyl-phenyl)sulfonyl-8-quinolyl]piperidin-4-ol;1-[3-[3-(Difluoromethoxy)phenyl]sulfonyl-8-quinolyl]piperidin-4-ol;(3S)-1-[3-(Benzenesulfonyl)-8-quinolyl]pyrrolidin-3-ol;1-[3-[3-(Difluoromethoxy)phenyl]sulfonyl-8-quinolyl]piperidine-4-carboxylicacid; (3S,4S)-1-[3-(Benzenesulfonyl)-8-quinolyl]pyrrolidine-3,4-diol;(3R)-1-[3-(3-Fluorophenyl)sulfonyl-8-quinolyl]pyrrolidin-3-ol;(3R,4R)-1-[3-(Benzenesulfonyl)-8-quinolyl]piperidine-3,4-diol;1-[3-(2-Methoxy-5-methyl-phenyl)sulfonyl-8-quinolyl]piperidin-4-ol;(3R,5 S)-1-[3-(Benzenesulfonyl)-8-quinolyl]piperidine-3,5-diol;1-[3-(Benzenesulfonyl)-8-quinolyl]piperidine-4-carboxylic acid;1-[2-[(8-Fluoro-3-quinolyl)sulfonyl]phenyl]azetidin-3-ol;1-[3-(2-Methoxyphenyl)sulfonyl-8-quinolyl]azetidin-3-ol;1-[3-(2-Methoxy-5-methyl-phenyl)sulfonyl-8-quinolyl]azetidin-3-ol;(3S,4R)-1-[3-(Benzenesulfonyl)-8-quinolyl]piperidine-3,4-diol;(3R,4S)-1-[3-(Benzenesulfonyl)-8-quinolyl]pyrrolidine-3,4-diol;(3R,4S)-1-[3-(Benzenesulfonyl)-8-quinolyl]-3-fluoro-piperidin-4-ol;1-[3-[3-(Trifluoromethyl)phenyl]sulfonyl-8-quinolyl]azetidine-3-carboxylicacid; (3R,4R)-1-[3-(Benzenesulfonyl)-8-quinolyl]pyrrolidine-3,4-diol;1-[3-(3-Trifluoromethyl-benzenesulfonyl)-quinolin-8-yl]-piperidine-3-carboxylicacid amide;1-[3-(3-Cyanophenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylic acid;1-[3-(3-Carbamoylphenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylicacid; 1-[3-(3-Carboxyphenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylicacid; 1-[3-(m-Tolylsulfonyl)-8-quinolyl]piperidine-4-carboxylic acid;1-[3-[3-(Trifluoromethoxy)phenyl]sulfonyl-8-quinolyl]piperidine-4-carboxylicacid; 1-[3-(3-Fluorophenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylicacid;1-[3-(3-Pyrrolidin-1-ylphenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylicacid;1-[3-[3-(3-Methoxypyrrolidin-1-yl)phenyl]sulfonyl-8-quinolyl]piperidine-4-carboxylicacid;1-[3-(3-Piperazin-1-ylphenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylicacid;1-[3-[3-(4-Methylpiperazin-1-yl)phenyl]sulfonyl-8-quinolyl]piperidine-4-carboxylicacid;2-[1-[3-[3-(Trifluoromethyl)phenyl]sulfonyl-8-quinolyl]-4-piperidyl]aceticacid;2-[1-[3-[3-(Trifluoromethyl)phenyl]sulfonyl-8-quinolyl]-3-piperidyl]aceticacid; or an N-oxide, tautomeric form, stereoisomer, or stereoisomericmixture; or pharmaceutically acceptable salt thereof.
 40. The method asclaimed in claim 39, where the disorders are selected from the groupconsisting of diseases of the central nervous system, addiction andobesity.
 41. The method as claimed in claim 40, where the disease of thecentral nervous system is a cognitive dysfunction.
 42. The method asclaimed in claim 41, where the cognitive dysfunction is associated withAlzheimer's disease.
 43. The method as claimed in claim 41, where thecognitive dysfunction is associated with schizophrenia.